bluuebunny/crossref_metadata_2025 huggingface dataset:
Imfirst: A phase IIIb, safety, single arm study of carboplatin (CB) or cisplatin (CP) plus etoposide (ET) with atezolizumab (ATZ) in patients with untreated extensive-stage small cell lung cancer (ES-SCLC) in Spain—Primary safety results of the induction phase.
Authors: García Campelo Maria Rosario , Domine Manuel , De Castro Javier , Moreno Alberto , Ponce Aix Santiago , Arriola Edurne , Carcereny Enric , Majem Margarita , Huidobro Vence Gerardo , Esteban Emilio , Fuentes Pradera Jose , Massuti Bartomeu , Ortega Ana Laura , Mónica Guillot , Cordoba Juan Felipe , Fernandez Natalia , Alonso Ruben , Crama Leonardo , Lerones Natalia , Cobo Manuel
Published: June 2021

8567

Background: Clinical trial (CT) IMpower133 met both primary endpoints and is the first CT to show significant clinical improvement over standard chemotherapy (C) with a good safety profile in first line (1L) ES-SCLC. The addition of ATZ to CB + ET resulted in an OS landmark of 34% and 22% compared to 21% and 16.8% of patients alive at 18 and 24 months respectively versus C. IMfirst evaluates ATZ + CB or CP + ET in a broader patient population than the pivotal study. ECOG Performance status (PS) 2, asymptomatic untreated brain metastases, underlying stable autoimmune diseases and HIV+ pts are eligible. IMfirst also includes the possibility of 6 C induction cycles according to investigator´s choice and consolidation radiotherapy. Methods: To evaluate the safety and efficacy of ATZ added to CB or CP + ET as 1L treatment in an interventional real world setting of ES-SCLC. Exploratory endpoints include tumor biomarker analysis related to ATZ. Results: As of Oct 2020, 117 pts had been enrolled, 105 treated with ATZ + CB + ET and 12 with ATZ + CP + ET. The median age was 65 years (Y) (range 35-89); 84 males; 14 pts (12%) had CNS metastases and 66 pts were current smokers and 50 former smokers, one had never smoked. The PS was 0 in 28 pts (24%), 1 in 75 (64%) and 2 in 14 (12%). The median of cycles of ATZ received was 4 for all the pts (range 1-12) and 2 for the pts (40) in maintenance phase (range 1-8). Number of pts with adverse events (AEs) was 109, 36 with Serious Adverse Events (SAEs) and 63 with AEs. 8 pts had SAEs related to treatment, 4 had adverse events of special interest and 13 pts discontinued the treatment due to AEs: 6 to ATZ, 12 to CB or CP and 10 to ET, 1 patient discontinued ATZ due to a related AE. Table shows the treatment related AEs (TRAEs). No grade 5 TRAEs were reported. Conclusions: IMfirst induction phase analysis confirms the safety profile of ATZ plus C in a broader population of patients. Efficacy, biomarker and further safety analyses will be presented in the future with longer follow up.[Table: see text]
First long-term results on efficacy and safety of long-acting pasireotide in combination with everolimus in patients with advanced carcinoids (NET) of the lung/thymus: Phase II LUNA trial.
Authors: Baudin Eric , Berruti Alfredo , Giuliano Mario , Mansoor Wasat , Bobirca Catalin , Houtsma Erik , Fagan Niamh , Oberg Kjell E. , Ferolla Piero
Published: June 2021

8574

Background: Everolimus (EVE) improves progression-free survival (PFS) in patients (pts) with progressive non-functioning thoracic and digestive advanced neuroendocrine tumors (NET). The LUNA trial aimed to assess the efficacy and safety of long-acting pasireotide (PAS) and EVE alone or in combination in pts with progressive bronchial or thymic carcinoids. Core phase results for primary endpoint (PFS) and secondary endpoints at 9 and 12 months (mo) were previously published. Cumulative data results at the end of the extension phase are presented here. Methods: LUNA was a prospective, multicenter, randomized, open-label, 3-arm, phase II trial. Adult pts with carcinoids of lung/thymus were randomized (1:1:1) to receive either PAS (60 mg/mo i.m.) or EVE (10 mg/day orally) or PAS + EVE. The key secondary endpoints assessed in this extension phase, including all the patients who were still not progressing at 12 months, were PFS, duration of biochemical response (DBR), and biochemical PFS (BPFS). Results: Of the total 124 pts included in the core phase, 41 pts with a median age of 61 years entered the extension phase including PAS (12), EVE (14) and PAS + EVE (15). Lung was the primary site of cancer in 95.1% and 82.9% had non-functioning tumors. Surgery/local or regional therapy was the preferred prior treatment in 63.4% pts. Disease progression was the primary reason for discontinuation among 3 arms with 65.9% in overall extension phase; no pts in PAS arm discontinued due to adverse events (AEs). Mean relative dose intensity (RDI) was higher for PAS (95.6% alone and 90.4% in combination) when compared to EVE (76.6% alone and 72.4% in combination); 38.1% pts in the EVE arm and 43.9% pts in the combination arm with EVE had RDI <70%. PAS +EVE combination showed clinical benefit in terms of PFS and BPFS compared to PAS and EVE alone as shown in Table. At least one dose reduction of PAS or EVE was reported in >50% pts. Most common AEs of any grade regardless of the study drug in PAS +EVE arm were hyperglycemia (87.8%), diarrhea (80.5%), and weight loss (58.5%), while stomatitis was reported in 34.1%. Twelve deaths were reported during the study and up to 56 days from last study treatment dose. Duration of exposure and efficacy. Conclusions: Mature median PFS and BPFS data suggest a benefit of PAS+EVE combination. The safety and tolerability profile of PAS and EVE alone or in combination were consistent with prior experience of these treatments in the oncology setting, with no new safety signals being reported during the study. Post-hoc prognostic studies are ongoing. Clinical trial information: NCT01563354. [Table: see text]
Clinicogenomic characterization of metastatic thymic epithelial tumors.
Authors: Ardeshir-Larijani Fatemeh , Radovich Milan , Schneider Bryan P. , Loehrer Patrick J.
Published: June 2021

8579

Background: Thymic epithelial tumors (TET) are one of the rarest adult malignancies. Overall, patients have favorable survival outcomes, however a small subset develop metastatic disease. Genomic characterization of this very rare, clinically aggressive TET subset is lacking. Herein, we evaluated the clinical and genomic characteristics of metastatic TET (mTET) compared to a large cohort (n = 117) of primary TET (pTET) from The Cancer Genome Atlas (TCGA). Methods: From 2015 to 2020, 52 pts with mTET underwent clinical CLIA-based sequencing using either whole-exome (n = 35), panel-based testing (n = 13) and/or liquid biopsy (n = 22). The specimen was taken from a metastatic organ (n = 34) or relapsed primary mediastinal mass (n = 14); 4 pts had liquid bx only. Data on pTET was derived from the TCGA. Kaplan-Meier and log-rank test was used for assessment of PFS, OS. Results: The median age was 56 yrs in mTET (range 32-74) vs. 60 yrs (range 17-84) in TCGA data. The M/F (%) was 40/60 in mTET and 48/52 in TCGA, respectively. Of note, 13 mTET pts had other types of cancer prior or concurrent with TET diagnosis (4-breast, 2-bladder, 5-other) in which radiotherapy (n = 4) and/or chemotherapy (n = 3) was administered prior to TET diagnosis. In our cohort, 19 pts had stage IVA and 33 pts had stage IVB (most common metastatic site was liver in 17 pts). WHO histologic classification was: A = 1, A/B = 3, B1 = 4, B2 = 10, B3 = 12, TC = 18, TC with neuroendocrine feature = 3, and lymphoepithelial carcinoma = 1. WHO B3 and TC histologies were more common in our cohort of mTET than in the TCGA cohort (63% (33/52) vs. 17% (20/117), respectively). Pts with TC had worse mOS compare to thymoma (109m vs. 163m, HR = 2.78, P = 0.04). The most common genomic alteration in mTET was TP53 (n = 17, 33%) compared to 3% in TCGA. This was followed by CDKN2A (n = 5, 10%), PIK3CA (n = 4, 8%), CDKN2B (n = 3, 6%) and NF1 (n = 3, 6%). All TP53 missense mut functionality was analyzed with polyphen-2 software and 91.6% (22/24) had 98-100% damaging probability. 70% of pts that harbored TP53 muts were TC (41%) or B3 (29%) histology. Clinically actionable genomic alterations targetable with available or investigational agents (e.g. high TMB; gain-of-function mutations in PIK3CA, CDK4, and mTOR; loss-of-function mutations in NF1) were seen in 23% (12/52) of pts. Conclusions: Patients with mTET are associated with more aggressive WHO histology (B3 and TC). Greater frequency of TP53 mutations are observed in mTET compared to pTET. Clinically actionable genomic alterations are frequently seen in mTET suggesting value in the routine sequencing of these patients.
Outcomes of anti-PD-(L1) therapy in combination with chemotherapy versus immunotherapy (IO) alone for first-line (1L) treatment of advanced non-small cell lung cancer (NSCLC) with PD-L1 score 1-49%: FDA pooled analysis.
Authors: Akinboro Oladimeji , Vallejo Jonathon Joseph , Mishra-Kalyani Pallavi Shruti , Larkins Erin A. , Drezner Nicole Lauren , Tang Shenghui , Pazdur Richard , Beaver Julia A. , Singh Harpreet
Published: June 2021

9001

Background: IO + chemotherapy ± anti-angiogenics comprise FDA-approved 1L regimens for metastatic NSCLC, with IO-only therapy approved only for PD-L1-positive NSCLC. Patients with PD-L1 scores 1-49% have many therapeutic options, and little is known about how subgroups of patients experience benefit across treatment regimens. Methods: Data was pooled from 8 randomized controlled trials investigating anti-PD-(L)1 therapy as IO-only or in chemo-IO regimens for the 1L treatment of patients with advanced NSCLC. PD-L1 score was defined as the proportion of tumor cells stained by the assay, and analysis was conducted for patients whose tumors had PD-L1 score 1-49%. Tumor-infiltrating immune cell staining was not considered. OS and PFS were compared between chemo-IO and IO alone via a pooled analysis. Median survival times were estimated using Kaplan-Meier methods. Hazard ratios were estimated using Cox proportional hazards models stratified by trial and adjusted for age, sex, race, ECOG, histology and smoking status. Results: A total of 2108 patients with NSCLC and PD-L1 score 1-49% were identified for this analysis. Baseline characteristics were: 37% aged 65-74 years and 12% aged ≥75; 67% male; 79% white; 65% ECOG ≥ 1; and 85% smokers. Median follow-up was 12.1 months. This pooled analysis showed that patients receiving chemo-IO (N=639) had longer PFS and OS compared to patients treated with IO alone (N=529), with median PFS 7.7 vs 4.2 months (HR 0.60; 95% CI 0.48, 0.76) and median OS 21.4 vs 14.5 months (HR 0.68; 95% CI 0.52, 0.90). All results presented are considered exploratory and hypothesis generating. Conclusions: This exploratory pooled analysis suggests that chemo-IO may improve efficacy outcomes over IO alone in most subgroups of patients with advanced NSCLC with PD-L1 score 1-49%. Patients 75 and over experienced similar outcomes across therapeutic options.[Table: see text]
Overall survival and exploratory subgroup analyses from the phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated KRAS p.G12C mutated non-small cell lung cancer.
Authors: Skoulidis Ferdinandos , Li Bob T. , Govindan Ramaswamy , Dy Grace K. , Shapiro Geoffrey , Bauml Joshua , Schuler Martin H. , Addeo Alfredo , Kato Terufumi , Besse Benjamin , Anderson Abraham , Ang Agnes , Ngarmchamnanrith Gataree , Tran Qui , Velcheti Vamsidhar
Published: June 2021

9003

Background: In the registrational phase 2 CodeBreaK 100 trial, sotorasib demonstrated an objective response rate (ORR) of 37.1% (95% Cl: 28.6, 46.2) and a median progression-free survival (PFS) of 6.8 months (95% Cl: 5.1, 8.2) in patients with pretreated KRAS p.G12C mutated non-small cell lung cancer (NSCLC). Tumor response was observed in patients bearing co-mutations in STK11, a driver of poor clinical outcomes with standard of care. Here, we report efficacy across an extended set of patient subgroups by key baseline characteristics and biomarkers. Methods: Sotorasib was given orally at 960 mg once daily to eligible patients who had advanced NSCLC harboring KRAS p.G12C and received prior standard therapies. Primary endpoint was ORR assessed by central review. Key secondary endpoints included PFS, overall survival, and safety. KRAS p.G12C mutant allele frequency (MAF) and tumor mutational burden (TMB) were analyzed by next-generation sequencing (NGS) using tissue samples. Mutational status of individual genes was determined by NGS using tissue and/or plasma samples. Correlations between response and KRAS p.G12C MAF, TMB, or co-mutations were analyzed in subsets of patients who had available respective results. Association between MAF and response was reported by odds ratio (95% CI), from a logistic regression with dependent variable of log odds of being a responder and an independent variable of MAF in a unit of 10%. Results: ORR across subgroups is presented in the Table. Response was independent of KRAS p.G12C MAF in the study population (odds ratio [95% CI]: 1.11 [0.88, 1.39]). OS remained immature. Conclusions: In the exploratory analyses of the phase 2 CodeBreaK 100 trial, the clinical benefit of sotorasib was observed across patient subgroups. Overall survival and updated exploratory analyses will be presented. Clinical trial information: NCT03600883. [Table: see text]
Racial disparities in biomarker testing and clinical trial enrollment in non-small cell lung cancer (NSCLC).
Authors: Bruno Debora S. , Hess Lisa M. , Li Xiaohong , Su Eric Wen , Zhu Yajun Emily , Patel Monaliben
Published: June 2021

9005

Background: Cancer racial disparities may exist at many levels in the health care system, from screening to timely diagnosis and treatments received, as well as clinical trial enrollment. This study investigated differences in black versus white race among patients with NSCLC undergoing biomarker testing and clinical trial enrollment in the US. Methods: This retrospective observational study utilized the Flatiron Health database, which includes longitudinal data of patients with advanced/metastatic NSCLC. Patients were eligible if they had evidence of systemic therapy in the database from 1/1/2017 through 10/30/2020. Descriptive analyses summarized differences by race in biomarker testing and trial enrollment. Multivariable regression examined the relationship between these factors. Results: A total of 14,768 patients were eligible: 9,793 (66.3%) were white and 1,288 (8.7%) were black. 76.4% of white patients and 73.6% of black patients underwent at least one single molecular test or comprehensive genomic analysis (p = 0.03). Next-generation sequencing (NGS) was performed among 50.1% of white patients and 39.8% of black patients (p < 0.0001. Trial participation was observed among 3.9% of white and 1.9% of black patients (p = 0.0002). There was a statistically significant association between race (white vs black) and both biomarker testing (ever vs never) and trial participation (yes vs no) (both p < 0.001, unadjusted chi square). Differences in NGS testing, baseline biomarker testing, and race were retained as statistically significant (p < 0.01) in adjusted regression analyses. The receipt of first-line targeted therapy was comparable between white and black patients (10.2% and 9.2%, respectively, p = 0.24); however, this summary did not consider biomarker test results. First line use of pembrolizumab+carboplatin+pemetrexed was observed among 19.8% of white and 22.6% of black patients; carboplatin+paclitaxel was observed among 16.5% and 18.6%, and single-agent pembrolizumab was observed among 14.8% and 11.5%, respectively. Conclusions: The use of NGS-based testing, which is recommended by the National Comprehensive Cancer Network Clinical Guidelines in Oncology for patients with advanced/metastatic NSCLC, is the most notable disparity among black patients, with more than a 10 percentage-point difference in receipt of this testing versus white counterparts. This may in part contribute to the more than double the rate of participation in clinical trials observed among white patients, as many second line and beyond trials utilize molecular targets as inclusion criteria. While multiple factors are known to impact health care disparities, access to and receipt of appropriate biomarker testing may be an attenable goal in order to ensure equal access to quality care.
Clinical outcomes for plasma-based comprehensive genomic profiling versus tissue testing in advanced lung adenocarcinoma.
Authors: Page Ray D. , Drusbosky Leylah , Dada Hiba I. , Raymond Victoria M. , Daniel Davey B. , Divers Stephen G. , Reckamp Karen L. , Villalona-Calero Miguel Angel , Odegaard Justin Iver , Lanman Richard B. , Papadimitrakopoulou Vassiliki , Leighl Natasha B.
Published: June 2021

9027

Background: Somatic genomic testing is recommended by numerous expert guidelines to inform targeted therapy treatment for patients with advanced lung adenocarcinoma (aLUAD). The NILE study was a prospective observational study that demonstrated non-inferiority of cell-free circulating tumor DNA (cfDNA)-based tumor genotyping compared to tissue-based genotyping to find targetable genomic alterations in patients with newly diagnosed aLUAD. As the cohort has matured, clinical outcomes data can now be reported. Methods: This prospective, multicenter North American study (NCT03615443) enrolled patients with previously untreated aLUAD who had standard of care (SOC) tissue genotyping performed and concurrent comprehensive cfDNA analysis using the commercially available Guardant360 assay (Guardant Health, Redwood City, CA). After 12 months of study enrollment, objective response rates, disease control rate, and time to treatment data were collected for patients with targetable genomic alterations, as defined by NCCN guidelines, who were treated with physician’s choice of therapy. Results: Among 282 patients on the study, 89 (31.6%) had an actionable biomarker detected by tissue (21.3%) and/or cfDNA (27.3%) analysis. Sixty-one (68.5%) of these patients were treated with an FDA-approved targeted therapy guided by somatic genotyping results ( EGFR, ALK, ROS1). Thirty-three patients were eligible for clinical response evaluation and demonstrated an objective response rate of 58% and disease control rate of 94%. Twenty-five (76%) achieved a durable response > 6 months; 17 (52%) achieved a durable response > 12 months. Patients responded to targeted therapy regardless of the variant allele frequency of the target alteration. The time to treatment (TtT) was significantly faster for cfDNA-informed biomarker detection as compared to tissue genotyping (median 18 vs 31 days, respectively; p = 0.0008). Conclusions: This is the first prospective community-based study to find that cfDNA detects guideline-recommended biomarkers at a rate similar to tissue genotyping, and therapeutic outcomes based on plasma-based comprehensive genomic profiling are comparable to published tissue-based targeted therapy clinical outcomes. The NILE study complements and confirms findings in the prospective FLAURA and SLLIP studies, which exclusively enrolled at academic sites. Clinical trial information: NCT03615443.
Second-line nintedanib plus docetaxel for patients with lung adenocarcinoma after failure on first-line immune checkpoint inhibitor combination therapy: Initial efficacy and safety results from VARGADO Cohort C.
Authors: Grohé Christian , Wehler Thomas , Dechow Tobias , Henschke Sven , Schuette Wolfgang , Dittrich Ina , Hammerschmidt Stefan , Müller-Huesmann Harald , Schumann Christian , Krüger Stefan , Atz Judith , Kaiser Rolf
Published: June 2021

9033

Background: The treatment landscape in advanced non-small cell lung cancer (NSCLC) has undergone significant changes, with immune checkpoint inhibitor (ICI) +/- chemotherapy now the preferred first-line (1L) regimen for metastatic, non-mutated NSCLC. However, only limited clinical data are available to guide subsequent treatment selection. Nintedanib (Vargatef), an oral triple angiokinase inhibitor targeting the vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR) pathways, is approved in the EU and other countries in combination with docetaxel for the treatment of advanced adenocarcinoma NSCLC after failure on 1L chemotherapy. Methods: This analysis is part of the ongoing, prospective, non-interventional VARGADO study (NCT02392455) of nintedanib + docetaxel. Here, we present initial efficacy and safety results from 100 patients (pts) with adenocarcinoma NSCLC in Cohort C, who received second-line (2L) nintedanib + docetaxel after failure on prior 1L ICI in combination with chemotherapy. Results: In Cohort C, the median age was 63 years (range: 43–84); 58 pts (58.0%) were men, and 71 pts (71.0%) had ECOG PS 0/1. Ninety-five pts (95.0%) had received prior 1L pembrolizumab-based combination therapy. Thirty-nine pts (39.0%) had progressed within 6 months after the start of 1L therapy, and 66 pts (66.0%) had progressed within 9 months. Objective response rate with 2L nintedanib + docetaxel was 37.3% (22/59 pts), disease control rate was 67.8% (40/59 pts), and median progression-free survival (PFS) was 4.4 months (95% confidence interval [CI]: 2.6–6.6). Among pts who had experienced disease progression < 9 months after the start of 1L therapy (n = 66), median PFS from the start of 2L nintedanib + docetaxel was 4.1 months (95% CI: 2.5–6.6). Among pts with disease progression ≥9 months after the start of 1L therapy (n = 34), median PFS from the start of 2L nintedanib + docetaxel was 8.5 months (95% CI: 2.4–not estimable). Grade ≥3 treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs leading to treatment discontinuation were observed in 47 pts (47.0%), 37 pts (37.0%) and 28 pts (28.0%), respectively. Conclusions: Initial data from VARGADO Cohort C provide the first evidence that 2L nintedanib + docetaxel has encouraging and clinically meaningful efficacy, and a manageable safety profile in pts with advanced adenocarcinoma NSCLC following progression on 1L ICI in combination with chemotherapy. Clinical trial information: NCT02392455.
Complete metabolic response in advanced non-small cell lung cancer patients with prolonged response to immune checkpoint inhibitor therapy.
Authors: Christoph Daniel Christian , Ferdinandus Justin , Metzenmacher Martin , Kessler Peter , Umutlu Lale , Aigner Clemens , Kambartel Karl-Otto , Grünwald Viktor , Eberhardt Wilfried Ernst Erich , Fendler Wolfgang Peter , Herrmann Ken , Faehling Martin
Published: June 2021

9050

Background: Recently reported, extended follow-up data from KEYNOTE-024 or -010 indicates that non-small-cell lung cancer (NSCLC) patients can experience long-term benefit from immunotherapy irrespective of discontinuation (per protocol: 35 cycles ∼24 months) or type of response in computed tomography (CT). Similar results were observed in the pooled analysis of 5-year follow-up data from CheckMate-017 and -057. This raises the question, whether patients may safely discontinue immunotherapy after achieving durable response. However, recently published results from CheckMate-153 demonstrated inferior survival rates in patients ceasing immunotherapy after one year, therefore optimal treatment duration of immunotherapy in advanced NSCLC remains unknown. Protocols from published Phase-III trials implemented treatment for a period of approximately 24 months or until evidence of disease progression or unbearable toxicity. Therefore, the ideal duration of immunotherapy remains unclear, and finding markers of beneficial outcome is of great importance. Here, we determine the proportion of complete metabolic responses (CMR) in patients that have not progressed after 24 months of immunotherapy. Methods: This is a retrospective analysis of forty-five patients with positron emission tomography using 2-[18F]fluoro-2-deoxy-D-glucose (FDG-PET) imaging for assessment of residual metabolic activity after at least 24 months of immunotherapy. Lesion-uptake in FDG PET on or below background level (using mediastinum as reference) was considered as CMR. Time until best objective morphological response including disease stabilization was measured from start of immunotherapy until first stable CT-scan (i.e. no progression or further response compared to previous scan) using RECIST 1.1. Results: Out of 45 patients, 29 patients had a CMR (64%). CMR was observed more frequently in non-first line patients. Patients with CMR were younger (median 65.7 vs. 75.5, P = 0.03). Fourteen patients with CMR have discontinued therapy and have not progressed until time of analysis; however median follow-up was only 5.6 (range 0.8-17.0) months. Conclusions: After a minimum of 24 months of palliative immunotherapy for NSCLC, CMR occurred in almost two thirds of patients. Potentially, achievement of CMR might identify patients, for whom palliative immunotherapy may be safely discontinued.
Taletrectinib (AB-106; DS-6051b) in metastatic non-small cell lung cancer (NSCLC) patients with ROS1 fusion: Preliminary results of TRUST.
Authors: Zhou Caicun , Fan Huijie , Wang Yongsheng , Wu Huijuan , Yang Nong , Li KunYan , Wang Xicheng , Qin Xintian , Yu Qitao , Fang Yong , Tao Min , Meng Xue , Han Baohui , Dong Xiaorong , Yan Bing
Published: June 2021

9066

Background: Taletrectinib (AB-106; DS-6051b) is a potent, selective ROS1/NTRK inhibitor. In two phase I trials, NSCLC patients (pts) with ROS1 fusion who received taletrectinib as first line ROS1 TKI had an objective response rate (ORR) of 66.7% (6/9) and median progression-free survival (PFS) of 29.1 mo (Sai-Hong Ignatius Ou et al., JTO Clinical and Research Reports, 2020). TRUST (NCT04395677) is an ongoing, multicenter, phase II study of taletrectinib in Chinese NSCLC pts with ROS1 fusion. Methods: The ROS1 TKI naïve or crizotinib pre-treated NSCLC patients with ROS1 fusion were treated with taletrectinib 400 or 600 mg QD. ROS1 testing was performed in each center and confirmed by central lab using RT-PCR. The primary endpoint was ORR (complete response [CR] + partial response [PR]) by IRC assessment. Secondary endpoints were disease control rate (DCR; CR + PR + stable disease), PFS and safety, etc. The pharmacokinetics (PK) of taletrectinib following 400 or 600 mg QD regimen was also evaluated. Results: As of the data cutoff (15 Jan 2021), 22 pts had received taletrectinib treatment. Median age was 54.5 years (range, 32-77 years;); 18.2% (4/22) had central nervous system metastases; ECOG performance status was 0 in 13.6% (3/22) of pts and 1 in 86.4% (19/22) of pts. Most pts (54.5%, 12/22) had prior systematic chemotherapy; 31.8% (7/22) of pts had prior crizotinib treatment. ORR by investigator among the crizotinib naïve pts with tumor assessment (N = 11) was 100% (95% CI, 72%-100%); 81.8% (18/22) of pts had treatment-emergent adverse events (TEAEs), including nausea, vomiting, diarrhea, transaminase elevation, white blood cell count decrease/neutrophil count decrease, etc. 13.6% (3/22) were grade ≥ 3, including fatigue (4.5%, 1/22), white blood cell decrease (4.5%, 1/22) and transaminase elevation (4.5%, 1/22).TEAEs led to dose interruption in 3 pts (13.6%), including dose reduction in 2 pts (9.1%). Taletrectinib in plasma approximately reached steady state on Cycle 1 Day 8 with 2- to 3- fold accumulations of exposure, which was consistent with results observed in the phase I trials. Conclusions: Taletrectinib demonstrated promising clinical activity with high ORR and good tolerability in ROS1 fusion positive NSCLC patients. The safety and PK profiles following taletrectinib treatment was generally consistent with the phase I trials. Clinical trial information: NCT04395677. Clinical trial information: NCT04395677.
CNS activity of poziotinib in NSCLC with exon 20 insertion mutations.
Authors: Le Xiuning , Garassino Marina Chiara , Cornelissen Robin , Socinski Mark A. , Tchekmedyian Nishan , Molina Julian R. , Baik Christina S , Leu Sharon , Dreiling Lyndah , Lebel Francois M. , Clarke Jeffrey Melson
Published: June 2021

9093

Background: Treatment addressing non-small cell lung cancer (NSCLC) harboring EGFR or HER2 exon 20 insertion mutations remains an unmet need. These tumors are associated with a high incidence of CNS metastases and unfavorable survival rates. Poziotinib is a potent, irreversible, tyrosine kinase inhibitor (TKI) with a structure that can overcome the steric hindrance of the exon 20 limited binding pocket. Preclinical data suggest poziotinib CNS penetration, and here we show meaningful poziotinib CNS activity in patients with NSCLC harboring exon 20 insertion mutations in an ongoing multi-cohort, multi-center Phase 2 study (ZENITH20; NCT03318939). Methods: ZENITH20 enrolled previously treated and naïve patients with advanced/metastatic NSCLC and EGFR or HER2 exon 20 insertion mutations in several cohorts: Cohort 1 (C1) EGFR previously treated; Cohort 2 (C2) HER2 previously treated and Cohort 3 (C3) EGFR treatment-naïve. All patients with stable CNS metastases at baseline were included. Poziotinib (16 mg) was administered orally QD, with follow-up for up to 24 months. The primary endpoint was Objective Response Rate (ORR) evaluated centrally using RECIST v1.1 by an independent image review committee. Secondary endpoints included Disease Control Rate (DCR), Duration of Response (DOR), Progression-Free Survival (PFS) and safety. Primary efficacy results have been previously released. Intracranial response was determined based on the modified RECIST criteria. Results: A total of 284 patients across 3 cohorts (C1 n=115; and C2 n=90; and C3 n=79) with a median age of 60.5 years were enrolled. The median follow-up was 7.3, 8.3, and 9.2 months for all patients in C1, C2, and C3, respectively. In NSCLC patients that had baseline CNS lesions (N=36), the analysis showed a patient-based ORR of 22.2% (8/36) and a DCR of 88.9% (32/36). One patient in each cohort had a complete intracranial response and stable disease was 80.6% across 3 cohorts and 92.9% in C2. Two patients each in C1 and C3 had progressive disease (PD) and none had CNS progression in C2 (Table). Conclusions: Poziotinib exhibited clinically meaningful CNS activity in patients with EGFR or HER2 exon 20 mutations in ZENITH20 Cohorts 1-3. The majority of the patients had no CNS progression and 3/36 patients had intracranial complete responses. The preliminary data suggest that poziotinib may provide a meaningful treatment alternative for patients with NSCLC that harbor EGFR or HER2 exon 20 mutations and who present with CNS metastases that have poor prognosis. Clinical trial information: NCT03318939. [Table: see text]
Optimal next-generation sequencing (NGS) panel for estimating tumor mutation burden (TMB) and its clinical implication for non-small cell lung cancer (NSCLC).
Authors: Ikeda Takaya , Oi Hajime , Yoh Kiyotaka , Matsumoto Shingo , Kato Terufumi , Nishino Kazumi , Nakamura Atsushi , Nakachi Ichiro , Sakakibara-Konishi Jun , Daga Haruko , Furuya Naoki , Taima Kageaki , Iwama Eiji , Ebi Noriyuki , Shibata Yuji , Izumi Hiroki , Nosaki Kaname , Zenke Yoshitaka , Goto Koichi
Published: June 2021

9097

Background: TMB estimation using targeted NGS panels is widely performed in clinical practice. The objective of this study was to determine the optimal NGS panel for estimating TMB and to evaluate its clinical implications for NSCLC. Methods: Two NGS panels, Oncomine Tumor Mutation Load Assay (OMLA) and FoundationOne (F1), were compared to select the most accurate TMB prediction panel. From February 2017 to May 2018, 350 lung cancer patients were analyzed by whole-exome sequencing (WES), and the concordance rate of OMLA and F1 to WES was examined. In addition, its clinical utility as a biomarker for immune checkpoint inhibitors (ICIs) was evaluated in our international genome screening network (LC-SCRUM-Asia). From June 2019 to December 2020, 3141 patients with NSCLC from 185 institutions were enrolled, and genomic analysis was successful. The clinico-genomic database of LC-SCRUM-Asia was used for this analysis. Results: The linear correlation with WES was 0.80 for OMLA and 0.78 for F1. This indicated that OMLA was more strongly correlated with WES. The cutoff value of F1 was 10 mut/Mb, which corresponded to 9 mut/Mb (OMLA) and 194 mutations (WES). The sensitivity of the OMLA for WES was 79%, and the specificity was 85%. Meanwhile, the sensitivity of the F1 was 74%, and the specificity was 80%. OMLA more accurately predicted TMB, and its clinical utility was evaluated. 3141 NSCLC patients, consisting of 2282 adenocarcinomas, 593 squamous cell carcinomas, and 266 others, were analyzed for TMB, estimated using OMLA. The median number of mutations was 4.2 mut/Mb (range, 0-718.4/Mb). High TMB (≥9 mut/Mb) was observed in 17.2% (393/2282) of adenocarcinoma cases and 25.8% (153/593) in squamous cell carcinoma cases. 778 patients were treated with ICI or ICI plus chemotherapy as the first-line treatment. Patients’ characteristics were as follows: male/female; 595/183, median age (range); 67 (25-90), stage II/III/VI/recurrence; 11/90/649/28, TMB high/low; 177/601, ICI/ICI plus chemotherapy; 114/664. The progression-free survival (PFS) was significantly longer in patients with high TMB than in those with low TMB (median PFS, 7.5 vs. 5.9 months, p = 0.0314). The overall survival (OS) was significantly longer in patients with high TMB than in those with low TMB (median OS, 27.4 vs. 20.4 months, p = 0.006). Conclusions: The TMB estimated by OMLA correlated more strongly with the WES-derived TMB comparing with F1. TMB estimated by OMLA was correlated with PFS and OS in NSCLC patients treated with ICIs. Prospective clinical trials are needed to determine whether TMB estimated by OMLA is a biomarker for ICI.
Real-world response and outcomes in NSCLC patients with EGFR exon 20 insertion mutations.
Authors: Ou Sai-Hong Ignatius , Lin Huamao Mark , Hong Jin-Liern , Yin Yu , Jin Shu , Lin Jianchang , Mehta Minal , Nguyen Danny , Neal Joel W.
Published: June 2021

9098

Background: There is currently no targeted therapy approved for patients with EGFR exon 20 insertion mutations (exon20ins) in NSCLC. Real world treatment outcome evidence for this rare population is limited. This study describes treatment patterns and outcomes in US patients with advanced NSCLC with EGFR exon20ins. Methods: The nationwide Flatiron Health electronic health record-derived deidentified database (cut-off 29 Feb 2020) was used to select 4 separate cohorts: (1) first-line (1L): patients receiving 1L therapy after documented exon20ins (1L start date as index date); (2) second or later line (≥2L): patients receiving ≥2L therapy after documented exon20ins (start date of ≥2L as index date); (3) ≥2L trial-aligned: ≥2L patients with baseline characteristics aligned with the key eligibility criteria of mobocertinib Trial NCT02716116 Part 3; and (4) ≥2L post platinum: ≥2L trial-aligned patients previously treated with platinum-based chemotherapy. Real-world endpoints were: confirmed overall response rate (cORR), PFS, and OS. Additional analyses were conducted for patients treated with immune-oncology therapy (IO). Results: Of 237 EGFR exon20ins patients, 129 patients were included in 1L cohort and 114 were in ≥2L cohort, including 63 ≥2L trial-aligned and 50 ≥2L post platinum patients. In 1L patients, EGFR TKI (28.7%) and platinum-based chemotherapy ± IO (56.6%) were the most common 1L regimens. In ≥2L patients, 28.1% received IO monotherapy, 17.5% received EGFR TKI, and 23.7% received platinum-based chemotherapy ± IO as index treatment. In the 1L setting, median PFS (mPFS) was 5.7 months for platinum-based chemotherapy and 4.5 months for IO + platinum-based chemotherapy. In the ≥2L setting, mPFS was 3.7 months for any therapy and 2.3 months for IO monotherapy. Full effectiveness data are provided in the accompanying table. Conclusions: This real world study provided a benchmark on the treatment outcome in patients with advanced NSCLC with EGFR exon20ins. Platinum-based chemotherapy was the most common 1L therapy and provided the longest mPFS. Immunotherapy, either as monotherapy or in combination with chemotherapy, appeared less effective for treatment of NSCLC with EGFR exon20ins. There is an unmet medical need for improved therapeutic options.[Table: see text]
Chronic immune checkpoint inhibitor (ICI) pneumonitis in patients (pts) with non-small cell lung cancer (NSCLC).
Authors: Stuart Jessica , Ricciuti Biagio , Alessi Joao Victor Machado , Nishino Mizuki , Awad Mark M.
Published: June 2021

9103

Background: ICI pneumonitis is an immune-related adverse event (irAE) of the lung and often requires discontinuation of ICI. While some pneumonitis cases resolve within the recommended 4-6-week period of corticosteroid therapy, others either fail to improve or have multiple flares necessitating longer or repeated courses of steroids. We investigated the clinical features and courses of pts with chronic pneumonitis. Methods: We analyzed 869 pts with NSCLC initiated on ICIs at our institution between 2011 and 2019 for development of ICI pneumonitis. Chronic pneumonitis was defined as any pneumonitis requiring a total of ≥12 weeks of steroids, given either continuously or over multiple courses of treatment. Cases of chronic pneumonitis in which the initial course of steroids lasted ≥12 weeks without interruption were termed “primary refractory pneumonitis”. Subsequent episodes of pneumonitis were categorized as either “recurrent pneumonitis” from ICI rechallenge or “pneumonitis flare” after steroid taper without ICI rechallenge. Chest CT scans were analyzed to classify the imaging patterns. Results: Of the 869 pts analyzed, 44 developed ICI pneumonitis (5.1%) and 22 of the 44 (50%) experienced chronic pneumonitis (Grade 2 in 11, Grade 3 in 9, and Grade 4 in 2). A cryptogenic organizing pneumonia (COP) pattern was the most common CT pattern among all pneumonitis cases (30/44) and in chronic pneumonitis cases (14/22). Among chronic pneumonitis cases, the median number of total weeks on corticosteroid therapy was 25.9 (range: 12.4 – 114.4 weeks). Four pts required additional immunosuppressive agents including mycophenolate or infliximab. Fourteen of 22 pts with chronic pneumonitis had primary refractory pneumonitis, while the remaining 8 pts were weaned off of steroids within 12 weeks but later developed additional episode(s) of pneumonitis, ultimately resulting in a total steroid duration of ≥12 weeks. The 14 pts with primary refractory pneumonitis had significantly shorter time to pneumonitis onset compared to the other 8 pts (median time to onset: 1.8 vs. 5.5 months, Wilcoxon ranksum p = 0.04). Seventeen of 22 patients had their ICI permanently discontinued; of these, 9 pts subsequently experienced pneumonitis flare after steroid taper, necessitating additional course(s) of steroid therapy. 5 of the 22 patients were rechallenged with ICI, and 4 of them had recurrent pneumonitis with ICI rechallenge. Conclusions: Half of the pts diagnosed with pneumonitis developed chronic pneumonitis requiring at least 12 weeks in aggregate of glucocorticoid therapy. Some patients had an initial prolonged steroid course while others initially improved and then flared, even after ICI discontinuation. Recognition of chronic pneumonitis as a distinct and common clinical entity is important in management of pts with ICI pneumonitis.
Overall survival in patients who received checkpoint inhibitors after completing tebentafusp in a phase 3 randomized trial of first-line metastatic uveal melanoma.
Authors: Orloff Marlana , Carvajal Richard D. , Shoushtari Alexander Noor , Sacco Joseph J. , Schlaak Max , Watkins Claire , Abdullah Shaad Essa , Goodall Howard , Butler Marcus O.
Published: June 2021

9526

Background: Tebentafusp (tebe) is a bispecific consisting of an affinity-enhanced T cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100+ cells. Tebe significantly improved OS compared to investigator’s choice (IC) in first line (1L) mUM [NCT03070392]. In a phase (ph) 2 study of tebe in 2L+ mUM (NCT02570308), several checkpoint inhibitor (CPI) refractory pts who were retreated with CPI after tebe achieved durable clinical benefit [1]. We therefore evaluated clinical outcomes of post-tebe CPI in patients treated on the ph3 trial of tebe versus investigator’s choice (IC) [NCT03070392]. Methods: In the ph3 trial, 378 HLA-A*02:01+ 1L mUM pts were randomized 2:1 to tebe (n=252) or IC (n=126) [pembrolizumab (82%), ipilimumab (12%) or dacarbazine (6%)]. No crossover to tebe was permitted, investigators were free to choose subsequent therapy, and there was no re-randomization at time of subsequent therapy. This analysis was conducted on the first interim analysis (data extracted Nov-2020). When pts received more than one subsequent therapy, the first was used in these analyses. Medians and 1-yr OS from the start of post-study therapy are obtained from standard Kaplan-Meier analyses; hazard ratios (HR) are from Cox regression models adjusted for age and gender. Results: 106/252 (42%) tebe pts received ≥ 1 subsequent therapy: 35% CPI, 9% chemo, 6% liver directed therapy (LDT), 6% other. 55/126 (44%) of IC pts received ≥ 1 subsequent therapy: 21% CPI, 10% chemo, 12% LDT, 10% other. Median time to first subsequent therapy was longer for tebe pts at 5.2 mo vs. IC pts at 3.8 mo. The median duration from start of first subsequent CPI to end date was longer in the prior tebe pts at 4 mo vs prior IC pts at 2.8 mo. From the start of any first subsequent therapy, prior tebe pts had longer OS compared to prior IC pts, HR 0.67 (95% CI 0.42, 1.07). Most of the subsequent therapy was CPI, and the OS benefit was also seen in this subset, HR 0.62 (95% CI 0.34, 1.14). For prior tebe pts, the median and 1-yr OS rates from start of any first subsequent therapy were 13 mo and 53% and from start of first subsequent CPI were 16 mo and 63%. Both were higher than the sequence of IC followed by any therapy (11 mo and 44%), IC followed by CPI (9 mo and 47%) and a recent meta-analysis of 2L+ mUM (7 mo and ̃35% 1-yr OS rate). Conclusions: Pts who progressed on tebe and then received CPI had better OS compared to pts who progressed on IC and then received CPI. Further analysis will explore whether confounding factors are influencing this effect. These exploratory data suggest that tebe, relative to IC, may improve outcomes to subsequent CPI. (1)Yang J. et al. ASCO 2019, J . Cli n Oncol 37:15_suppl, 9592. Clinical trial information: NCT03070392.
The use of cryoablation to overcome resistance to PD-1 blockade in unresectable melanoma.
Authors: Mooradian Meghan , Fintelmann Florian J. , Kaufman Howard E. , Mino-Kenudson Mari , Barth Jaimie Lynn , Lawless Aleigha , Sharova Tatyana , Fadden Riley , Rubin Krista M. , Lawrence Donald P. , Frederick Dennie T. , Sade-Feldman Moshe , Sullivan Ryan J.
Published: June 2021

9538

Background: Percutaneous image-guided cryoablation (cryo) is an established minimally invasive oncologic treatment that modulates the immune microenvironment. We hypothesized that cryo can augment anti-tumor responses in melanoma patients progressing on immune checkpoint inhibitors (ICI). Methods: In this non-randomized phase II single-center study, subjects with unresectable melanoma progressing on ICI underwent cryo of an enlarging lesion and ICI continuation for a minimum of 2 additional cycles. Computed tomography was performed at 6-8 weeks following cryo to determine tumor response in non-ablated lesions per RECIST1.1, with confirmatory scans at 8-12 weeks. The primary endpoint was safety and feasibility. Secondary endpoints were overall response rate (ORR) and disease control rate (DCR) with DCR defined as the percentage of pts who achieve complete response (CR), partial response (PR), and stable disease (SD). Correlative analyses on pre- and post-cryo tumor biopsy and blood samples were performed. Results: From May 2018 through July 2020, 20 pts were screened, 18 enrolled and 17 treated per protocol. All pts received prior PD-1/PD-L1 monotherapy and 12 (67%) experienced primary resistance to ICI. Median follow-up was 8.5 months. Ablated lesions included lymph nodes (n = 4), lung/pleura (n = 4), soft tissue/bone (n = 3), adrenal (n = 3), chest wall (n = 1), and kidney (n = 1). Peri-procedural events occurred in 3 cases (pneumothorax, diaphragm puncture, osteomyelitis). One pt. with underlying ICI-induced hypophysitis experienced an adrenal crisis post-procedure, which rapidly corrected with stress-dose steroid administration; there were no de novo immune-related adverse events post-ablation and there were no grade 4/5 events. In evaluable pts (n = 17), ORR was 18% and DCR was 47% (3 PR, 5 SD). To investigate the inflammatory state of the tumor microenvironment prior to cryo, PD-1, CD8+ TIL IHC, was performed and will be presented at the meeting. Additional exploratory analyses (serial ctDNA analysis, single cell RNA sequencing, HLA-subtyping) are ongoing. Conclusions: Cryoablation in patients with unresectable melanoma following progression on ICI is feasible with an acceptable side effect profile. Efficacy data of this potentially synergistic approach in metastatic melanoma is encouraging. Correlative analyses are underway to identify biomarkers of response to this novel strategy. Clinical trial information: NCT03290677. [Table: see text]
KEYNOTE-555 Cohort B: Efficacy, safety, and PK of pembrolizumab (pembro) 400 mg every 6 weeks (Q6W) as 1L therapy for advanced melanoma.
Authors: Jacobs Conrad R. , Rapoport Bernardo Leon , Chan Sze Wai , Ruff Paul , Arance Ana Maria , Mujika Karmele , Anderson James Robert , Lala Mallika , Jain Lokesh , Akala Omobolaji Oyekunle , Chartash Elliot , Cohen Graham Lawrence
Published: June 2021

9541

Background: In KEYNOTE-555, a model-based approach suggested expected drug exposure with pembro 400 mg Q6W is similar to that observed with approved doses of pembro 200 mg or 2 mg/kg Q3W. The pembro Q6W dose is now approved. We present interim efficacy, safety and PK of 1L pembro 400 mg Q6W for patients (pts) with advanced melanoma in KEYNOTE-555 Cohort B (NCT03665597). Methods: Eligible pts had unresectable stage III or IV melanoma, ECOG PS ≤1, and no prior systemic therapy for advanced disease.Pts received pembro 400 mg Q6W for up to 18 cycles (≈2 years).The primary efficacy endpoint was ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included PFS by BICR per RECIST v1.1 and safety. PK profile and exposure were evaluated for cycle 1 and steady state (cycle 4). Results: Between May 2019 and Jan 2020, 101 pts were enrolled and received ≥1 dose of pembro. Baseline characteristics were generally similar to pt cohorts of historical pembro studies in advanced melanoma. As of the data cutoff date of August 6, 2020, all pts had ≥6 mo of follow-up and 40.6% of pts had discontinued study treatment. Median (range) duration of treatment and doses administered were 8.2 mo (1 day–13.9 mo) and 6 (1–11) doses, respectively. Observed exposure with pembro 400 mg Q6W had lower variability than model predictions and was within PK parameters from clinical experience with other pembro regimens (Table). ORR was 50.5% (95% CI 40.4–60.6). 12.9% of pts had CR and 37.6% had PR. Median PFS was 13.8 mo (95% CI 3.0–not reached). Estimated PFS rates were 56.5% at 6 mo and 54.3% at 12 mo. Treatment-related AEs of any grade occurred in 79.2% of pts (grade 3–4: 6.9% of pts; no deaths due to a treatment-related AE). The most common immune-mediated AEs were hyperthyroidism (6.9%) and hypothyroidism (6.9%). Conclusions: 1L treatment with pembro 400 mg Q6W yielded a clinically meaningful ORR in pts with advanced melanoma. PK, efficacy and safety results from KEYNOTE-555 Cohort B support prior findings from the model-based assessment and indicate that the benefit-risk profile for the more practical pembro 400 mg Q6W regimen is consistent with that of 200 mg or 2 mg/kg Q3W regimens. Clinical trial information: NCT03665597. [Table: see text]