bluuebunny/crossref_metadata_2025_split huggingface dataset:
Actionability of comprehensive genomic profiling (CGP) compared to single-gene and small panels in patients with advanced/metastatic non-small cell lung cancer (aNSCLC): A real-world study.
Authors: Bapat Bela , Sweetnam Connor , McBratney Ashleigh , Izano Monika A. , Schroeder Brock , Walters Sheetal , Chen William , Febbo Phillip G. , Berry Anna B. 
Published: June 2022

e21114 Background: Biomarker testing for patients with aNSCLC includes testing for specific alterations in single genes, hotspot multigene panels, or CGP. Historically, CGP has been used following progression on early lines of systemic therapy to identify genomic alterations not captured by single-gene/hotspot testing, or to determine clinical trial(CT) eligibility. We compared the proportion of patients with genomic alterations for which FDA has approved targeted therapies(TT) (actionable alterations) identified through CGP vs. single-gene/small panel(“small panel”) testing in the real-world setting. Methods: In a retrospective study, patients initially diagnosed-with/progressed-to aNSCLC between 1/1/2015-12/31/2020, treated in the US community health setting, were categorized based on small panel or CGP testing. Patients were followed until the earliest of last contact/death/study-end on 9/30/2021. Testing between 30 days prior to initial NSCLC diagnosis and end of follow-up was used to determine actionability based on OncoKB levels, and eligibility for two basket-CTs(ASCO-TAPUR, NCI-MATCH). Results: Of 7,242 aNSCLC patients in this study, 5,154 (72%) received molecular testing (50% only small panel; 14% CGP; and 7% with an unknown size panel), 22% of patients remained untested and 7% were tested for only PD-L1. Among CGP-tested patients evaluated for tumor mutational burden (TMB), 18% were classified as TMB-High. > 75% of patients presented with advanced cancer at initial diagnosis, 51% were female, 50% were White, and median age was 68 years. Molecular testing rate increased from 9% to 20%(CGP) and 42% to 51%(small panel) between 2015–2020. The proportion of patients with ≥1 actionable biomarker was significantly higher with CGP than small panels (34%vs.15%; p < 0.001). Of tested patients. the proportion of CT eligible patients was also significantly greater for CGP than small panels (56%vs.4%; p < 0.001). The proportion of tested patients that received an FDA-approved TT or immunotherapy(IO) within 30 days of testing was higher in CGP cohort compared to small panel (9%vs.3%; p < 0.001). Conclusions: Although rates of CGP and small panel testing are increasing over time, overall molecular testing remains underutilized, and the proportion of patients who received TT/IO post-testing is low. Use of CGP is associated with higher identification of actionable biomarkers and patients receiving TT/IO, and CT eligibility.
Phase Ib/IIa study evaluating the safety and clinical activity of osimeritinib combined with anlotinib in EGFRm, treatment-naive advanced NSCLC patients (AUTOMAN).
Authors: Han Baohui , Yan Bo , Gu Aiqin , Chu Tianqing , Zhang Wei , Wang Huiming , Zhong Hua , Shi Chunlei , Zhang Xueyan 
Published: June 2022

e21140 Background: Limited data is known regarding osimertinib plus anlotinib as first line treatment in EGFRm advanced NSCLC patients. Earlier we have reported that osimertinib in combination with anlotinib was well tolerated. Here we further present the efficacy and safety profile of the combined therapy. Methods: In this phase Ib/IIa, open-label study, treatment-naïve patients with an activating EGFR mutation, advanced or metastatic lung adenocarcinoma were eligible. Patients with stable CNS metastases were allowed to enroll. Patients were treated with anlotinib at dose of 8mg, 10mg and 12mg, all patients received osimertinib 80mg. Primary endpoint was objective response rate (ORR) by investigator using RECIST v1.1. Secondary endpoints include disease control rate (DCR), depth of response, median progression free survival, overall survival rate at 12 months and safety profile. Data cut-off: Nov. 23rd, 2021. Results: From November 2020 through June 2021, 25 patients were enrolled in the study and started treatment. Median age was 59 years (38-77years), 11 (44%) were female, 24 (96%) were ECOG PS 1. 24 (96%) patients were stage IV and 6 (24%) had CNS metastases. At DCO, 18 (72%) patients remained on treatment. Among 23 response evaluable patients, the overall ORR was 65.2% (95%CI 42.7,83.6), DCR was 95.7% (95%CI 78.0,99.9) and median depth of response was -40.7% (range, -70.6 to 49.7). Adverse events (AEs) were observed in 21 (84%) patients. The most common AEs were platelet count decreased (56.5%), thyroid-stimulating hormones increased (39.1%) and diarrhea (30.4%), no unexpected AEs occurred. Grade≥3 AEs and SAEs were experienced by 5 (20%) and two (8.0%) patients, respectively. Dose reduction occurred in 8 (32%) patients and all were related to anlotinib. There was no fatal AE event reported in this study. Conclusions: Osimertinib in combination with anlotinib as first-line treatment for naïve EGFRm advanced NSCLC patients showed encouraging antitumor activity with manageable safety profile. The study is ongoing and more results will be updated in the future. Clinical trial information: NCT04770688.
Complete evaluation of resistance mechanisms to first-line osimertinib requires tissue biopsy.
Authors: Piotrowska Zofia , Piper-Vallillo Andrew , Banwait Mandeep , Hung Yin P , Rao Revati , Muzikansky Alona , Meador Catherine Belle , Hata Aaron N. , Sequist Lecia V. 
Published: June 2022

e21154 Background: Osimertinib (osi) is the preferred 1st line (1L) therapy for patients (pts) with EGFR-mutant NSCLC, but acquired resistance is universal. Identification of mechanisms of resistance (MoR) to 1L osi can inform subsequent treatment strategies. Here, we report MoRs identified at our institution from tissue and/or liquid biopsy (bx) upon 1L osi progression. Methods: We included pts seen at MGH with advanced EGFR+ NSCLC who had tissue and/or liquid bx (for ctDNA analysis) obtained at progression on 1L osi. Molecular testing was performed using local next-generation sequencing (NGS) and, when available, MET/ EGFR FISH. We retrospectively collected clinical characteristics, tissue histology and NGS results. Results: 54 pts (38 Female; median age 61 yrs) had tissue (n = 35) and/or liquid (n = 32) bx upon progression on 1L osi between November 2016-January 2022. 13/54 pts had both tissue and ctDNA testing. Primary EGFR mutations included del19 (32), L858R (16) and other (6). Median time from osi start to 1st resistance bx was 12.3 mos (range, 1-37). MoRs are summarized in the table. Among 35 pts with tissue bx, histologic transformations (trans) were the most common MoR, seen in 23% pts, including both small cell histology (tSCLC; 5/35), squamous histology (tSqCC; 2/35) and 1 pt with both SCLC + SqCC features in one bx. Among 5 pts with tSCLC and pre-trans NGS, only 2 had baseline TP53/RB1 loss. MET amp was seen in 20% tissue (including one with tSqCC) and secondary EGFR mutations in 9%; 43% of tissue bx had no identified MoR. Among 32 pts with ctDNA NGS, secondary EGFR mutations (16%) were the most prevalent MoR, with MET amp seen in 13%. 65% pts had no MoR by ctDNA. 6/13 pts with both tissue and ctDNA had concordant findings (MET amp-2, EGFR L718Q – 1; No MoR - 3). As expected, the 2 pts with tSCLC had no MoR in ctDNA. In 2 cases, MET amp was seen in tissue but not ctDNA; the converse was true in 1 pt. Conclusions: Histologic transformations were the most common MoR to first-line osimertinib accounting for 23% tissue biopsies and, in 3/5 pts, occurred in the absence of the known risk factor of baseline TP53/RB1 loss. In this small cohort, MET amp was more commonly seen in tissue than in ctDNA, and 63% of liquid biopsies showed no detectable MoR. Our findings suggest that tissue biopsy is critical for complete evaluation of MoRs in pts progressing on first line osimertinib, and that tissue and ctDNA may be complementary.[Table: see text]
Clinical efficacy and safety of individualized pembrolizumab administration based on pharmacokinetic in advanced non-small cell lung cancer: An open-label, single-arm, exploratory clinical trial.
Authors: Wang Na , Zheng Lie , Li Meichen , Hou Xue , Zhang Baishen , Chen Jing , Chen Likun 
Published: June 2022

e21161 Background: Pembrolizumab with or without chemotherapy has become the standard therapy in advanced non-small cell lung cancer (NSCLC), with a fixed dose of 200mg every 3 weeks. We performed this study to explore the clinical efficacy and safety of pharmacokinetic (PK)-guided pembrolizumab administration in advanced NSCLC. Methods: In this prospective, open-label, single-arm exploratory study, we enrolled advanced NSCLC patients without sensitizing EGFR or ALK mutation in Sun Yat-Sen University Cancer Center. Eligible patients received pembrolizumab 200mg every 3 weeks with or without chemotherapy for four cycles, then for patients without progressive disease, pembrolizumab was administrated in new dose-intervals (T) until disease progression. We set the effective concentration (Ce) at 15μg/ml and new dose-intervals (T) was calculated according to steady state plasma-concentration (Css) of pembrolizumab using following equation: Css × 21D = Ce (15μg/ml) ×T. Primary endpoint was the progression-free survival (PFS), secondary endpoints were objective response rate (ORR), and safety. Besides, advanced NSCLC patients who regularly received pembrolizumab 200mg 3-weekly until disease progression and more than four cycles in our center were respectively enrolled as the history-controlled cohort. Patients with Css of pembrolizumab also underwent genetic polymorphism analysis of variable number of tandem repeats region (VNTR) in neonatal Fc receptor (FcRn). This study is registered at Clinicaltrials. gov, NCT05226728. Results: Between Nov 2019 and Dec 2020, total 58 patients were enrolled and received pembrolizumab 200mg every 3 weeks with or without chemotherapy, and 33 patients further received pembrolizumab in new adjusted dose-intervals according to Css after four cycles. The Css of pembrolizumab ranged from 11.01 to 61.21 μg/ml, 30 patients need prolonged intervals (22-80d) and 3 shortened intervals (15-20d). In PK-guided cohort, the median PFS was 15.1 months (95%CI 10.2-20.0 months) and ORR 57.6%, whereas the median PFS in history-controlled cohort was 7.7 months (95% CI 5.1-10.2 months) and ORR 48.2%. The immune-related adverse events occurred in 15.2% of patients in PK-guided cohort and 17.9% of patients in history-controlled cohort. The VNTR3/VNTR3 genotype of FcRn had significantly higher Css of pembrolizumab than VNTR2/VNTR3 ( p= 0.005). Conclusions: PK-guided pembrolizumab administration showed promising clinical efficacy and manageable toxicity, which provided an alternative rational therapeutic strategy of pembrolizumab in advanced NSCLC. Clinical trial information: NCT05226728.
Limited benefit from the addition of immunotherapy to chemotherapy in TKI-refractory EGFR-mutant lung adenocarcinoma.
Authors: Hong Lingzhi , Lewis Whitney E , Varghese Susan , Rivera Melvin , Du Robyn , Chen Pingjun , Kemp Haley , Rinsurongkawong Waree , Rehmani Sadiq , Spelman Amy R. , Elamin Yasir Y , Negrao Marcelo Vailati , Sepesi Boris , Gibbons Don Lynn , Lee J. Jack , Wu Jia , Vokes Natalie I , Heymach John , Zhang Jianjun , Le Xiuning 
Published: June 2022

e21169 Background: The benefit of adding immunotherapy to chemotherapy in EGFR-mutant lung adenocarcinoma (LUAD) with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is not fully investigated. This study aimed to explore the outcomes of immunotherapy combinations in such population in a real-world setting. Methods: This retrospective analysis included patients with EGFR-mutant LUAD who progressed on EGFR TKIs and received subsequent therapy with chemotherapy (chemo; n = 84), chemotherapy with immunotherapy (chemoIO; n = 30), chemotherapy plus bevacizumab with or without IO (withBev; n = 42), and IO monotherapy (IO-mono; n = 22). Clinical progression-free survival (cPFS) from the start of the therapy to discontinuation was assessed. Associations of clinical characteristics with cPFS were evaluated using univariable and adjusted Cox regression models. Results: A total of 178 patients (mean age = 62.6; 57.9% females) with a median cPFS (mcPFS) of 4.9 (95% CI: 4.4-5.4) months with 162 (91%) progression events. There was no difference in cPFS between chemoIO vs chemo groups (5.3 months vs 4.8, P = 0.8). Compared to the chemo group, patients who were treated withBev trended towards better PFS (6.1 months vs 4.8; P = 0.3; HR 0.79; 95% CI: 0.52-1.20;), while patients with IO-mono had inferior PFS (2.2 months; P = 0.001; HR 2.22; 95% CI: 1.37-3.59). Patients who were administered one-line of TKI prior to subsequent therapy acquired better PFS when compared to those with multiple prior TKIs (5.2 months vs 4.5; P = 0.011; HR 0.66; 95% CI: 0.48-0.91). The significance remained the same after adjusted by other clinicopathological variables including post-TKI treatment strategies and metastatic status (P = 0.005). Furthermore, among the chemoIO group, patients with PD-L1 expression had better PFS (n = 15, 7.7 months vs 4.5, P = 0.04; HR 0.36; 95% CI: 0.13-0.96) than those without PD-L1 expression (n = 6). However, PD-L1 was not associated with PFS among the patients treated with chemoIO plus bevacizumab. Brain or liver metastases were associated with worse PFS. Conclusions: Immunotherapy adds limited benefit when combined with chemotherapy in TKI-refractory EGFR-mutant LUAD. Chemotherapy +/- bevacizumab are reasonable treatment options for these patients.
Clinical characteristics and molecular features of non-small cell lung cancers (NSCLCs) following disease progression on immune checkpoint inhibitors (ICIs).
Authors: Gainor Justin F. , Ravi Arvind , Awad Mark M. , Holton Mark , Arniella Monica , Stewart Chip , Freeman Samuel , Leshchiner Ignaty , Chow Andrew , Henick Brian S. , Velcheti Vamsidhar , Griffin Aaron Timothy , Ricciuti Biagio , Riess Jonathan W. , Janne Pasi A. , Hacohen Nir , Wolchok Jedd D. , Hellmann Matthew David , Getz Gad 
Published: June 2022

e21178 Background: ICIs are cornerstones of therapy for advanced NSCLC. Despite dramatic and sometimes durable responses to therapy, most patients (pts) either (i) do not respond to therapy (intrinsic resistance), or (ii) subsequently progress after initial clinical benefit (acquired resistance). Currently, insights into the molecular mechanisms of resistance to ICIs in NSCLC are lacking. Methods: To investigate clinical and molecular features of pts progressing on ICIs, we identified pts who underwent repeat tumor biopsies on and/or after disease progression on ICIs and were included in the Stand Up 2 Cancer (SU2C)/Mark Foundation multi-institutional cohort. Biopsy specimens underwent whole-exome sequencing (WES) and/or whole transcriptome sequencing (RNAseq). Results: We identified 37 pts who underwent a total of 47 repeat biopsies on or after ICIs. Six pts underwent multiple post-ICI biopsies (range 2-4). Twenty-five pts (68%) received PD-(L)1 inhibitor monotherapy, 6 (16%) received PD-(L)1 plus CTLA-4 inhibitors, and 6 (16%) received other PD-1 inhibitor-based combinations. Overall, the objective response rate was 46% among pts undergoing repeat biopsies (complete response 2 [5%], partial response 15 [41%], stable disease 14 [38%], progressive disease 5 [14%] and not evaluable 1 [3%]). Median progression-free survival (PFS) was 8.1 months. In total, pre-ICI biopsy specimens were available in 20 pts. WES and RNAseq were performed on 67 and 44 specimens, respectively. Median tumor mutation burden (TMB) in pre-ICI specimens was 5.0 mutations/Mb versus 4.9 mutations/Mb in post-ICI specimens ( p= 0.3, Mann-Whitney U test). Among 20 paired pre/post-ICI specimens, there was no significant difference in TMB (pre-treatment median 3.9 mutations/Mb; post-treatment median 4.3 mutations/Mb; p= 0.7, Wilcoxon signed-rank test). One pt with a complete response acquired a nonsense mutation in B2M, and one pt with a partial response acquired a nonsense mutation in JAK1. Among 10 paired pre/post-ICI specimens that underwent RNAseq, we observed significant decreases in granzyme B and perforin in post-ICI specimens ( p= 4×10-5 and p= 2×10-3, respectively, limma-voom analysis). Conclusions: Genomic alterations impairing antigen presentation (e.g., B2M) or immune activation (e.g., JAK1) may enable resistance to ICIs in a small subset of cases. However, the majority of repeat biopsies obtained from pts progressing on ICIs lacked clear genetic mediators of resistance, suggesting the presence of additional tumor-intrinsic and/or tumor-extrinsic factors underlying resistance to ICIs in NSCLC.
Melanoma of unknown primary: Favorable survival persists in the immunotherapy era.
Authors: Maharaj Satish , Jain Nikita , Albawaliz Anas , Miller Donald M. , Chesney Jason Alan 
Published: June 2022

e21513 Background: Patients with advanced melanoma have historically had better survival in those with unknown primary (MUP) than known primary (MKP). Trends in survival since the introduction of immunotherapy have not been established. Methods: We conducted a retrospective cohort study of patients with advanced/metastatic melanoma (Stage IIIC/IV disease) treated during the period 2014-2020 at the University of Louisville. The primary outcome was overall survival in MUP compared with MKP. Differences in clinical characteristics, BRAF status, tumor mutational burden and PD-L1 tumor proportion score (Dako 22C3 assay) were examined. Differences between numerical variables were calculated based on parametric or non-parametric comparisons accordingly and categorical data analyzed using chi-squared testing. Kaplan-Meier survival analyses were performed with log-rank testing to evaluate differences. Alpha was set at 0.05 for significance. Results: Of the 79 patients with advanced/metastatic melanoma included, 12 had MUP and 67 had MKP. Of those with MKP, the primary site was cutaneous melanoma in 65 and anal melanoma in 2. Clinical characteristics showed the majority were male, with median age of 61 years. There were no significant differences in demographics, distribution of stage, BRAF status, TMB, PDL-1 score or treatment modality between MUP and MKP groups (Table). The median follow-up time overall was 50 months. The MUP group demonstrated significantly better survival with 3-year OS of 92% vs. 62% in MKP, and 5-year OS of 83% vs 44% in MKP. Median survival was 54 months for MKP and not reached for MUP. For MKP, the 5-year OS of 44% compares similarly to other cohorts. The Keynote-001 trial of advanced/metastatic melanoma treated with pembrolizumab reported 5-year OS of 41%. This is approximately a 4-fold improvement compared to cohorts treated before the approval of immunotherapy, where the 5-year OS was in the range of 10% [Lee et al, 2009]. The 5-year OS for metastatic MUP was previously in the range of 18%, also suggesting improvement by about 4-fold with the use of immunotherapy. Conclusions: Melanomas of unknown primary continue to have better survival with durable response on immunotherapy even in the advanced/metastatic setting. The exact mechanisms for this survival advantage remain unknown but are likely immune-mediated.[Table: see text]
ANKRD36 mutation as a negative predictor for melanoma immunotherapy.
Authors: Chen Bing , Guo Shizhou , Xing Xiaodan , He Qianru , Zhang Qin , Duan Qianqian , Sun Tingting , Qi Chuang 
Published: June 2022

e21517 Background: Melanoma is one of the most aggressive and immunogenic tumors. Current immunotherapies using immune checkpoint inhibitors such as CTLA4 and PD1 to stimulate T cell-mediated tumor killing significantly improved the overall survival of patients with metastatic melanoma. However, the clinical predictors of response to these therapies are still not fully characterized. Previous studies have shown that the high gene expression of Ankyrin repeat domain 36 (ANKRD36) can lead to the occurrence and poor prognosis of colon cancer and kidney cancer. In this study, we aimed to explore the role of ANKRD36 mutation in the prognosis of melanoma immune checkpoint inhibitors (ICIs). Methods: Public data of patients treated with ICIs(ipilimumab) from Van Allen (n = 110) cohort were obtained and analyzed. In survival analysis, Kaplan-Meier curves were compared by log-rank test, and the hazard ratio (HR) was determined through a multivariable Cox regression model. The potential mechanism was subsequently explored through RNA expression data from The Cancer Genome Atlas (TCGA). Results: The frequency of ANKRD36 mutation in the Van Allen cohort and TCGA cohort was 7.2% (8 in 110) and 1.56% (7 in 448) respectively. We further analyzed the Kaplan Meier curve and multiple Cox regression model of the Allen cohort and found that the survival of the mutant type in immunotherapy was significantly shorter than that of the wild-type group (PFS: HR = 3.09 [95% CI: 1.47, 6.51], p = 0.002; OS: HR = 2.33 [95% CI: 1.12, 4.86], p = 0.02). Both mutant type and tumor metastasis would have negative effects on immunotherapy(PFS: HR = 3.66 [95% CI: 1.71, 7.85], p < 0.001***; OS: HR = 3.16 [95% CI: 1.47, 6.82], p = 0.003**). Analysis of the transcriptome data from the TCGA database found that resting CD4 memory T cells is highly expressed in ANKRD36 mutant patients (p = 0.032), which may indicate that the patient's immune system did not activate the anti-tumor immune mechanism. Conclusions: In our study, the frequency of ANKRD36 mutations was investigated in clinical and TCGA cohorts, which may provide useful information for guiding patient treatment. ANKRD36 mutation may be a negative predictor of ICIs in patients with melanoma and play a role in prognosis.