bluuebunny/crossref_metadata_2025 huggingface dataset:
Atezolizumab plus stereotactic ablative therapy for medically inoperable patients with early-stage non-small cell lung cancer.
Authors: Kelly Karen , Daly Megan Eileen , Mirhadi Amin , Lara Frances , Garcia Leslie A , Chen Shuai , Eastham David , Wiegner Ellen Anderson , Riess Jonathan W. , Schalper Kurt A. , Monjazeb Arta
Published: May 2020

9011

Background: Stereotactic ablative radiation therapy (SABR) is the standard-of-care for medically inoperable, early stage non-small cell lung cancer (NSCLC), but regional and distant failures remain problematic. Based on our in vivo data showing synergy between radiation and immune checkpoint inhibitors (ICI) and the known efficacy and mild toxicity profile of ICI in NSCLC, we conducted a phase I study to determine the maximum tolerated dose of neoadjuvant, concurrent, and adjuvant atezolizumab with SABR for early stage NSCLC patients (pts). Methods: Eligible pts had histologically confirmed T1-3 NSCLC with at least one feature predictive of increased recurrence risk: diameter ≥1 cm, SUV ≥6.2 on PET, or moderately/poorly differentiated histology, were medically inoperable or refused surgery and had a Zubrod PS ≤2. Patients received 6 cycles of atezolizumab. A 3+3 dose finding design was employed with 3 dose levels: 3 mg/kg, 10 mg/kg, and 1200 mg flat dosing. SABR was delivered starting cycle 3 to 50 Gy over 4-5 fractions. Dose limiting toxicity (DLT) was assessed during the first 9 weeks. Results: 20 pts were enrolled, 15 pts in the dose finding and 5 pts at the recommended phase II dose (RP2D). Patient factors: MedIan age 77; 45% male, 85% smoking history, 85% PS 0-1 and 35% squamous. One pt on dose level 2 had a DLT – a grade 3 rash. Atezolizumab 1200 mg flat dosing was the RP2D. Grade 3 pneumonitis was not observed. Partial responses after 2 cycles were seen in 3/17 evaluable pts (18%) and 1 pt had a minor response. No patient progressed on treatment. PD-L1 expression was 0% 8/13 (62%), >1% - 50% 4/13 (31%), >50% 1/13 (8%) in pts with sufficient tissue. Of 5 pts with PD-L1 expression 3 (60%) were responders and 1 (12.5%) of 8 pts with 0% PD-L1 expression responded. Multi-plex Quantitative Immunofluorescence (QIF) using a T cell activation panel demonstrated to correlate with ICI response was performed on 9 samples (including 2 responders, 1 minor responder). The CD3 QIF score was > two-fold higher in the responders compared to non-responders, and the levels of proliferating and activated T cells were likewise > two-fold higher. Comprehensive stool and serial blood analyses have been completed. Correlative endpoints will be reported along with additional efficacy outcomes. Conclusions: Atezolizumab plus SABR is feasible, safe and shows an efficacy signal in medically inoperable early stage NSCLC. This combination will be tested in a randomized phase III trial SWOG/NRG S1914. Funding: This work was supported by the DOD CDMRP W81XWH-15-2-0063 and Genentech. Clinical trial information: NCT02599454.
YAP1 positive small-cell lung cancer subtype is associated with the T-cell inflamed gene expression profile and confers good prognosis and long term survival.
Authors: Owonikoko Taofeek Kunle , Dwivedi Bhakti , Chen Zhengjia , Zhang Chao , Barwick Benjamin , Gilbert-Ross Melissa , Ernani Vinicius , Barwick Benjamin , Zhang Guojing , Carlisle Jennifer W , Khuri Fadlo Raja , Curran Walter J , Lonial Sagar , Ramalingam Suresh S. , Sun Shi-Yong , Waller Edmund K. , Sica Gabriel
Published: May 2020

9019

Background: The dominant expression of transcription factors ASCL1, NeuroD1, YAP1 or POU2F3 characteristically defines four small cell lung cancer (SCLC) subtypes (SCLC-A, SCLC-N, SCLC-Y and SCLC-P). The clinical validation and biological relevance of these emerging SCLC subtypes is currently lacking. Methods: Using the Illumina TruSeq RNA Exome Kit, we generated RNA-Seq data from 61 cases of SCLC and pulmonary carcinoid to interrogate gene expression differences in SCLC subtypes as well as in survival outliers (top and bottom decile) matched for clinically relevant prognostic factors and treatment. We also assessed YAP1 protein expression in a blinded fashion by immunohistochemistry in 130 SCLC cases. Results: We successfully classified 68% of SCLC into one of the four SCLC subtypes whereas 81.5% of carcinoids did not fit into any of these categories. GSEA for differentially expressed genes between outlier subgroups showed significant upregulation of interferon gamma and interferon alpha response genes in late survivors. Moreover, a previously validated 18-gene T-cell inflamed gene expression profile was upregulated in late survivors and in the SCLC-Y subtype. Furthermore, the SCLC-Y subtype and late survivors showed higher expression of HLA gene family and reduced expression of cancer testis antigens. The median (95%CI) OS was 14 (4.3, 28.8), 16.7 (0.9, NA), 8.1 (2, 9.7) and 20.1 (0.6, 39.5) months respectively, for SCLC-A, N, P and Y subtypes. YAP-1 protein expression was positive in 17 of 130 (13%) SCLC cases. The majority of cases with positive YAP1 expression by immunohistochemistry, 12 of 17 cases (70.6%), were limited stage SCLC at the time of original diagnosis. Conclusions: SCLC subtypes have clinical implication as predictive and prognostic biomarker. SCLC-Y subtype is enriched for T-cell inflamed phenotype and long term survival, and may predict for clinical benefit of immunotherapy.
Detection of early-stage lung cancer by exhaled volatile organic compounds using a high-pressure photon ionization time-of-flight mass spectrometry.
Authors: Qiu Mantang , Li Hang , Meng Shushi , Li Qingyun , Zhou Zuli , Wang Jun
Published: May 2020

9030

Background: Exhaled breath-based test is an attractive option for cancer detection due to its non-invasive nature. Exhaled volatile organic compounds (VOCs) are produced in various biochemical processes and might be sensitive tumor biomarkers. Here, we reported an exploratory study to investigate the performance of exhaled VOCs for detection of early-stage lung cancer using a high-resolution high-pressure photon ionization time-of-flight mass spectrometry (HPPI-TOFMS). Methods: Treatment-naïve patients with pulmonary nodules who received surgery at our department and without history of cancer were enrolled. Exhaled breath samples were collected before surgery and stored in Tedla bags. A CO2 sensor was applicated during sample collection to ensure only “alveolar air” was collected. Exhaled samples were directly detected by HPPI-TOFMS, which has a resolution > 3000. Deep learning algorithm was used to build detection model based on HPPI-TOFMS data. Results: A total of 171 patients were included in this study, including 139 patients with lung cancer (114 of TNM stage I, 14 of stage II, 9 of stage III, and 2 of stage IV) and 32 patients with benign nodules. Mass spectrum peaks with m/z < 500 detected by HPPI-TOFMS were retained and 32500 features were extracted from each exhaled breath samples. Based these extracted features, participants who were pathologically diagnosed as lung cancer could be discriminated from those with benign diseases with an accuracy of 96.19%, sensitivity of 96.43%, and specificity of 84.38%. Discrimination of lung cancer patients with lymph node metastasis (n = 12) from those without lymph node metastasis (n = 127) had an accuracy of 83.23%. Conclusions: Exhaled VOCs as detected by a high-resolution HPPI-TOFMS might be sensitive biomarkers for detection of early-stage lung cancer.
CT and PET radiomic features associated with major pathologic response to neoadjuvant immunotherapy in early-stage non-small cell lung cancer (NSCLC).
Authors: Nakajima Erica C. , Leal Jeffrey P. , Fu Wei , Wang Hao , Chaft Jamie E. , Hellmann Matthew David , Pomper Martin , Forde Patrick M.
Published: May 2020

9031

Background: An early biomarker of response to immunotherapy (IO) is needed urgently to identify the patients (pts) who will derive benefit. We reported the first clinical trial of neoadjuvant IO (nIO) in resectable non-small cell lung cancer (NSCLC) (NCT02259621). In this study, we investigated whether there was an association between MPR and radiomic features (RF) in [18F]-fluorodeoxyglucose ([18F]-FDG) PET and standard CT images obtained at baseline and after nIO in early stage NSCLC tumors. Methods: Prior to receiving neoadjuvant nivolumab or nivolumab/ipilimumab, patients with Stage I-IIIA NSCLC underwent two [18F]-FDG PET-CTs and/or plain CTs: a baseline scan at enrollment (PRE), and after nIO (POST). After neoadjuvant treatment, tumors were resected and evaluated for MPR. Volumes of interest (VOIs) were drawn around primary tumors on the scans. Using our novel radiomic software, Imager-4D, VOIs were evaluated for 20 RFs assessing [18F]-FDG standard uptake value (SUV) or Hounsfield unit (HU) heterogeneity and spatial distribution in PET and CT images respectively. The baseline, post-treatment, and percent change in RFs before and after nIO were compared between tumors with and without MPR. Wilcoxon test was used for the comparisons. Results: The PRE and POST scans of 24 pts were analyzed. All pts had PRE and POST CTs performed, and 17 pts had PRE and POST [18F]-FDG PET-CT scans. 7 of 24 (29%) had MPR. In the CT scan analysis, HU-based RFs of voxel count, total volume, energy, entropy, homogeneity, contrast, and dissimilarity in POST CT scans each significantly association with MPR. In the PET scan analysis, SUV mean and voxel count RFs in the POST scans, and the percent change in the cluster shade RF between PRE and POST scans were significantly associated with MPR. Conclusions: Collectively, we identified a significant increase in heterogeneity in the POST CT images of NSCLC tumors that had MPR. This association may reflect increased T cell infiltration or tumor necrosis. In contrast, most [18F]-FDG-based RFs did not distinguish MPR vs non-MPR tumors, although the sample size was limited. We will further investigate these HU-based RFs as non-invasive markers of response to IO in conjunction with pathologic markers of IO response and in a larger patient cohort.
A retrospective evaluation of PD-L1 expression on primary non-small cell lung cancer (NSCLC) samples and associated involved hilar or mediastinal lymph nodes (N1 or N2) (REPLICA).
Authors: Karapanagiotou Eleni , Bille Andrea , Taniere Philippe , Flash Clare , Douiri Abdel , Willis Elizabeth , Kandasamy Srivani , Curinga Domenico , Velamuri Shriram , Nonaka Daisuke
Published: May 2020

9044

Background: Little is known about the PD-L1 expression in early stage NSCLC as well as the possible heterogeneity of PD-L1 expression in different sites. This study provides information on both PD-L1 expression in stage II and III NSCLC and the relationship between PD-L1 expression in the primary site (lung) and metastatic lymph nodes (LNs) N1 and/or N2. Methods: Samples (primary tumor and N1/N2) from 500 patients who underwent lung resection and lymphadenectomy for NSCLC without prior treatments were collected and analyzed for PD-L1 expression using the 22C3 pharmdx Agilent assay. The tumor proportion score (TPS) is documented for each sample according to the following categories: PD-L1: < 1%, 1-49%, ≥ 50%. PD-L1 stained slides were reviewed by two pathologists independently; for discrepant cases the two pathologists reviewed the stains jointly and the consensus score used for the data analysis. Agreement between the two pathologists was assessed by overall agreement and kappa statistic. The association between PD-L1 expression in the primary tumor and lymph node was assessed by cross-tabulation. Results: A total of 456 tumors and involved LNs were included in the analysis. Pathologist one assessed 435 primary tumor and LN pairs and pathologist 2 assessed 453 tumor and LNs pairs. The overall agreement between pathologists on PD-L1 expression in primary tumor samples was 77%; K = 0.59 (95% CI 0.57 – 0.63) and in LNs 83%; k = 0.62 (95% CI 0.56 – 0.70). Primary tumors showed PD-L1 < 1% in 235/422 (55,6%), PD-L1 1-49% in 146/422 (34,6%) and PD-L1 > = 50% in 41/422 (9.8%). 77% (327/422) showed no heterogeneity in PD-L1 expression between the primary tumor and involved LNs. In tumors with PD-L1 < 1% expression, 94% of the LNs showed PD-L1 < 1% expression and less than 1% showed PD-L1 > = 50%, 6% of the LNs showed PD-L1 1-49%. When the primary tumor was PD-L1 > = 50% nearly half (46%) of the involved LNs showed the same degree of PD-L1 positivity and 10% of them showed PD-L1 < 1%; 44% of the LNs showed PD-L1 1-49%. When the primary tumor showed 1-49% PD-L1 staining, 60% of the LNs showed the same staining pattern, 36% showed PD-L1 < 1% and only 4% showed PD-L1 > = 50% expression. Conclusions: In stage II and III NSCLC, half of the primary tumors show negative PD-L1 expression. Discrepant PD-L1 expression between primary tumors and LN metastases was seen in 23% of the cases, and when present, PD-L1 expression in LN tumors tended to be lower than that in primary tumors.
A mid-chemoradiation dynamic risk model integrating tumor features and ctDNA analysis for lung cancer outcome prediction.
Authors: Moding Everett J , Esfahani Mohammad Shahrokh , Nabet Barzin , Liu Yufei , Chabon Jacob J. , He Jianzhong , Qiao Yawei , Xu Ting , Yao Luyang , Gandhi Saumil , Liao Zhongxing X. , Das Millie , Ramchandran Kavitha , Padda Sukhmani Kaur , Neal Joel W. , Wakelee Heather A. , Loo Billy W. , Lin Steven H. , Alizadeh Ash A. , Diehn Maximilian
Published: May 2020

9046

Background: Circulating tumor DNA (ctDNA) molecular residual disease after curative intent therapy predicts disease progression in localized lung cancer. We hypothesized that integrating pre-CRT features and ctDNA levels during chemoradiation therapy (CRT) can predict patient outcomes earlier to enable response-adapted therapy. Methods: We identified pre-CRT features prognostic of disease progression after CRT for Stage II-III non-small cell lung cancer (NSCLC) in a historical “pre-CRT” training cohort of 109 patients. In addition, we applied CAPP-Seq ctDNA analysis pre-CRT and a median of 21 days into CRT (mid-CRT) to a “ctDNA” training cohort of 42 patients treated at MD Anderson and an independent validation cohort of 21 patients treated at Stanford. Prognostic pre-CRT features and mid-CRT ctDNA concentration were integrated using a Bayesian proportional hazards approach to generate a Continuous Individualized Risk Index (Kurtz et al. Cell 2019) for NSCLC (CIRI-NSCLC) to predict freedom from progression (FFP). Results: Adenocarcinoma histology (HR 2.6, P = 0.0005) and KEAP1 mutation (HR 2.7, P = 0.002) but not stage (P = 0.16), age (P = 0.60), or gender (P = 0.98) were significantly associated with FFP in the pre-CRT training cohort. Mid-CRT ctDNA concentration as a continuous variable was significantly associated with FFP in the ctDNA training cohort (HR 1.6, P = 0.04), and applying an optimal threshold identified in the training cohort (3.2 hGE/ml) significantly stratified FFP in the independent ctDNA validation cohort (HR 4.8, P = 0.02). CIRI-NSCLC enabled individualized real-time updating of the probability of FFP as model features became available over the course of CRT. CIRI-NSCLC outperformed individual model features in the independent validation cohort when compared by C-statistic (CIRI-NSCLC: 0.85; mid-CRT ctDNA: 0.76; histology: 0.66; KEAP1: 0.60). Across the whole cohort, patients with a greater than 66% risk of progression predicted by CIRI-NSCLC (n = 10) had an FFP of 10.0% at 12 months while patients with a less than 33% risk of progression predicted by CIRI-NSCLC (n = 22) had an FFP of 79.7% at 12 months (HR 15.0, P < 0.001). Conclusions: Our results suggest that CIRI-NSCLC can identify patients at very high and low risk of progression. Prospective evaluation will be necessary to test the potential utility of adapting treatment based on CIRI-NSCLC.
Phase II study of olaparib in malignant mesothelioma (MM) to correlate efficacy with germline and somatic mutations in DNA repair genes.
Authors: Hassan Raffit , Mian Idrees , Wagner Cathy , Mallory Yvonne , Agra Maria , Padiernos Emerson , Sengupta Manjistha , Morrow Betsy , Wei Jun S. , Thomas Anish , Steinberg Seth M. , Khan Javed , Ghafoor Azam
Published: May 2020

9054

Background: BRCA1 associated protein 1 ( BAP1), a nuclear deubiquitinase involved in DNA double-strand break repair is frequently mutated in MM. Because poly(ADP-ribose) polymerase inhibitors (PARPIs) induce synthetic lethality in BRCA1/2 mutant cancers, we sought to evaluate efficacy of olaparib in patients with MM and correlate it with pathogenic germline and somatic mutations in DNA repair genes. Methods: Phase II single-center study (NCT03531840) enrolled patients with advanced pleural or peritoneal mesothelioma who had progressed on prior therapies, age >18 years, ECOG performance status <1, adequate organ and bone marrow function. Olaparib 300mg was given twice daily orally in 3 week cycles until disease progression or toxicity. Efficacy was assessed by CT scan every 6 weeks using RECIST criteria. Whole exome sequencing (WES) was performed on blood and tumor samples to identify pathogenic germline and somatic mutations in DNA repair genes. Primary objective was to determine response rate based on germline or somatic mutation status of DNA repair genes. Results: Between July 2018 to May 2019, 23 patients were enrolled, 15 pleural and 8 peritoneal MM [14 male; median age 63 (range 41-75 years); median number of prior treatments 3 (range 1-5)]. Median olaparib cycles received was 4 (2-21). WES to identify pathogenic mutations in the germline and tumor was performed in 23 and 17 patients respectively. Four patients had germline BAP1, 1 germline MRE11A, and 5 had somatic BAP1 mutations. Of 22 evaluable patients, 1(4%) had partial response (PR), 17 (77%) had stable disease at 6 weeks and 4 (18%) had progressive disease. Patient with PR had a germline mutation in MRE11A. Median progression free survival (PFS) and overall survival (OS) for all patients was 3.4 months (95% CI: 2.7 – 4.8 months) and 8.1 months (95% CI: 4.5 months – not estimable) respectively. Median PFS of germline BAP1 mutant patients (n = 4) was 2.3 months (95% CI: 1.3 – 3.6 months) compared to 4.1 months (95% CI: 2.7 – 5.5 months) for BAP1wild type patients (n = 18;P = 0.026). Median OS was 4.6 months (95% CI: 3.1 – 4.9 months) for patients with germline BAP1 mutation versus not reached for those without germline BAP1 mutation (P = 0.0058). The most common side effects of olaparib were anemia (16%), lymphopenia (24%), nausea (14%), and increased creatinine (9%). Conclusions: Olaparib has limited anti-tumor activity in previously treated MM patients including those with germline or somatic BAP1 mutations. Presence of germline BAP1 mutations was associated with decreased PFS and OS. Clinical trial information: NCT03531840.
Genomic landscape and immune phenotype of malignant pleural mesothelioma.
Authors: Patel Meera , Elliott Andrew , Liu Stephen V. , Kim Chul , Raez Luis E. , Feldman Rebecca , Pai Sachin Gopalkrishna , Wozniak Antoinette J. , Nagasaka Misako , Lopes Gilberto , Spira Alexander I. , Kim Edward S. , Korn Wolfgang Michael , Mamdani Hirva
Published: May 2020

9056

Background: Malignant pleural mesothelioma (MPM) is a relatively uncommon malignancy with poor prognosis and no major therapeutic breakthroughs over the past decade. Better understanding of the genomic landscape and distribution of immune biomarkers in this disease has the potential to enable development of novel therapies. Methods: We analyzed molecular profiles of 222 MPM tumors using next-generation sequencing of 592 genes utilizing Caris Life Sciences platform. Genes were grouped into pathways: DNA damage repair (DDR) ( ATM, BRCA2, BRIP1, BAP1, CHEK2, ERCC2, FANCA/D2/E/L, MLH1, MSH6, MUTYH, NBN, PMS2, RAD50/51B, WRN), cell cycle regulation including TP53 ( RB1,CCNE1, CDKN2A, CCND1, CCND3, CDKN1B), chromatin remodeling (CR) ( ARID2, ASXL1, DNMT3A, EP300, EZH2, KDM6A, KMT2C, KMT2D, NSD3, PBRM1, SMARCB1/A4, SETD2), RAS/MAPK ( KRAS, MAP2K1, NF1, NF2), and PI3K/AKT ( AKT, PIK3CA, PIK3R1/R2, PTEN, RICTOR, TSC1, TSC2, ZNF703). Tumor mutational burden (TMB), PD-L1 expression (SP142 IHC, tumor staining), and MSI/MMR were analyzed. Seventy-two cases also had whole transcriptome sequencing data. Differences in alterations were compared for age, gender, and pathways. Results: Median age of patients (pts) was 72 yr (range, 37-90), 73% were male. Gene pathway alterations were seen in 81% of cases. DDR, specifically homologous recombination (HR), was the most commonly mutated pathway (36.9%), followed by RAS (25.2%) and CR (18.9%). Genes mutated in ≥5% of cases included BAP1 (26.3%), NF2 (23.5%), TP53 (15.5%), SETD2 (10.2%). PD-L1 was high (≥50% tumor cells positive) in 11.4% (n = 24), intermediate (1-49%) in 31.4% (n = 66), and negative ( < 1%) in 57.1% (n = 120) pts. TMB was high (≥10 mutations/Mb) in 9.6% of tumors (n = 20). None of the tumors were dMMR/MSI-H. HR gene BAP1 and CR gene SETD2 mutations trended to be more prevalent in pts ≥70 yo (p = 0.02). CR trended to be more commonly mutated in females (p = 0.02). No other significant differences were found in specific gene/pathway alterations, PD-L1 expression, or TMB in the context of age and gender. Distribution of PD-L1 expression was not different among various pathways. No highly recurrent, targetable fusion isoforms were seen among the 85 identified (mean 1.1 fusions/tumor), which have not yet been characterized for pathogenicity. Conclusions: The majority of MPM tumors harbor alteration in one of the key cellular pathways. HR pathway mutations are the most common. The majority of tumors were PD-L1 negative and carry low TMB indicating low immunogenicity. No age and gender specific differences exist except for BAP1 and SETD2 mutations.
Safety and efficacy of tazemetostat, an enhancer of zeste-homolog 2 inhibitor, in patients with relapsed or refractory malignant mesothelioma.
Authors: Zauderer Marjorie Glass , Szlosarek Peter Wojciech , Le Moulec Sylvestre , Popat Sanjay , Taylor Paul , Planchard David , Scherpereel Arnaud , Jahan Thierry Marie , Koczywas Marianna , Forster Martin , Cameron Robert B. , Peikert Tobias , Argon Evren Kocabas , Michaud Neil , Yang Jay , Kansra Vikram , Fennell Dean A.
Published: May 2020

9058

Background: Breast cancer gene 1 (BRCA1)-associated protein 1 (BAP1), a nuclear deubiquitinase, is commonly inactivated in malignant mesothelioma. Preclinical data showed that BAP1 inactivation sensitizes mesothelial cells to inhibition of enhancer of zeste-homolog 2 (EZH2), a methyltransferase implicated as an oncogenic driver in this tumor. This study evaluated the safety and efficacy of tazemetostat (TAZ), a potent and selective EZH2 inhibitor, in relapsed/refractory (R/R) malignant mesothelioma with BAP1-inactivation. Methods: EZH-203 (NCT02860286) was a 2-part, open-label, phase 2 study that assessed the pharmacokinetics (PK), safety, and efficacy of TAZ in pts with R/R malignant mesothelioma. In part 1, pts received TAZ 800 mg QD on day 1 (D1) and 800 mg BID, beginning day 2 of cycle 1 (C1). In part 2, pts received 800 mg of TAZ BID on D1 of C1. A two-stage Green-Dahlberg design was used for part 2. Primary endpoints were PK profiling of TAZ in all pts (part 1), and disease control rate (DCR) at week 12 in pts with BAP1-deficient R/R malignant mesothelioma (part 2). Secondary endpoints included safety, overall response rate (ORR), progression-free survival, overall survival, and duration of response (DOR). Results: The study enrolled 74 pts with R/R malignant mesothelioma, 70 pts (95%) were centrally confirmed to be BAP1-deficient. Median prior lines of therapy were 2 (range, 1-9). Observed clinical data in the presence of CYP3A4 inhibitors and inducers suggest a low DDI potential of TAZ. The 12 week DCR was 47% (n = 35). The ORR per RECIST version 1.1 was 3% [complete response: 0%; partial response (PR): 3% (n = 2)]. Of the 2 patients with PR, 1 had a DOR of 21 weeks and the other is ongoing (15.3 weeks at data cut off). 47 pts (64%) and 21 pts (28%) had stable disease (SD) and progressive disease, respectively. Overall, 91% pts discontinued, either due to disease progression (n = 65), death (n = 5), or treatment discontinuation (n = 1). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in ≤5% of patients, most commonly anemia (5%) and dyspnea (4%). No pts discontinued due to TEAEs. There were no treatment related deaths. Conclusions: Based on disease control rate and stable disease, TAZ showed antitumor activity in pts with BAP1-deficient R/R malignant mesothelioma. TAZ monotherapy was generally well-tolerated. The current data support further clinical evaluation of TAZ in these pts. Furthermore, this trial presents an optimal paradigm for drug development in molecularly-enriched cohorts in mesothelioma. Clinical trial information: NCT02860286.
Role of immunotherapy in stage IV large cell neuroendocrine carcinoma of the lung.
Authors: Komiya Takefumi , Powell Emily
Published: May 2020

9060

Background: Despite approvals of immune checkpoint inhibitors in both small cell and non-small cell lung cancers, role of immunotherapy in large cell neuroendocrine carcinoma (LCNEC) in lung is undefined. Methods: Using National Cancer Database (NCDB), Stage IV LCNEC cases diagnosed in 2014-2016 with at least 30-day follow up were analyzed. Clinical demographics included age (20-69 vs. 70+), sex (male vs. female), race (whites vs. others), insurance (uninsured vs. others), institution (academic vs. others), Charlson-Deyo score (0-1 vs. 2-3), brain metastasis (Yes vs. No), liver metastasis (Yes vs. No). Information regarding cancer treatment was limited to first course of therapy, including surgery for primary lesion (Yes vs. No), radiation (Yes vs. No), chemotherapy (Yes vs. No), and immunotherapy (Yes vs. No). Survival analysis was performed using Kaplan-Meier curves and Log-rank tests. Cox proportional hazard model was used for multivariate analyses. A two-sided p-value < 0.05 was considered as significant. Results: Among 661 eligible cases, 37 patients were treated with immunotherapy. No significant association between use of immunotherapy and clinical demographics was observed except for use of chemotherapy (p = 0.0008). Chemotherapy was administered in 34 (92%) and 406 (65%) of cases in immunotherapy and non-immunotherapy groups, respectively. Use of immunotherapy was associated with improved overall survival (Log-rank p = 0.0168). Landmark analysis in the immunotherapy group showed 12 and 18-month survival of 34.0% and 29.1%, respectively, as compared with 24.1% and 15.0% in the non-immunotherapy group Multivariate analysis demonstrated that female sex, presence of liver metastases, surgery, use of chemotherapy and immunotherapy (HR = 0.64, p = 0.0164) had significantly improved survival. Propensity score matching in overall survival showed a nonsignificant trend (p = 0.0733) in favor of immunotherapy group. Conclusions: This retrospective study using one of the largest cancer databases suggests that use of immunotherapy may improve survival of LCNEC patients. Prospective studies are warranted for further validation.
Phase II study of gedatolisib for small-cell lung cancer (SCLC) patients (pts) with genetic alterations in PI3K/AKT/mTOR pathway based on a large-scale nationwide genomic screening network in Japan (EAGLE-PAT/LC-SCRUM-Japan).
Authors: Udagawa Hibiki , Ikeda Takaya , Umemura Shigeki , Daga Haruko , Toyozawa Ryo , Harada Daijiro , Sakakibara-Konishi Jun , Morise Masahiro , Yamamoto Noboru , Takahashi Toshiaki , Kato Terufumi , Shingyoji Masato , Ushio Ryota , Hara Satoshi , Takata Saori , Nomura Shogo , Matsumoto Shingo , Niho Seiji , Sato Akihiro , Goto Koichi
Published: May 2020

9064

Background: Development of targeted therapy for SCLC based on a large-scale genomic screening is an innovative challenge. Gedatolisib is a highly potent dual inhibitor of PI3K/mTOR and is expected to have an effect for tumors with PI3K/AKT/mTOR pathway alterations. SCLC harboring this pathway alterations is rare. Thus, we conducted a phase II study based on a nationwide genomic screening network in Japan (LC-SCRUM-Japan) to develop novel targeted therapies. Methods: SCLC pts with targetable genetic alterations were screened at 154 institutions in Japan. A multicenter, single-arm phase II study was conducted to evaluate the efficacy and safety of gedatolisib in advanced SCLC pts with genetic alterations in the PI3K/AKT/mTOR pathway. The primary endpoint was objective response rate (ORR). The planned sample size was 19 (threshold and expected ORR of 20% and 50%, one-sided alpha of 5%, and power of 80%). Results: 930 SCLC pts were screened from July 2015 to January 2020. Targetable genetic alterations were identified in 148 pts (16%), including 53 PI3K/AKT/mTOR (6%), 81 MYC family (9%), 10 EGFR (1%) and 15 KRAS (2%). A total of 12 pts with genetic alterations in the PI3K/AKT/mTOR pathway (5 PIK3CA, 6 PTEN, and 1 AKT1 mutation) were enrolled in the phase II study. The median age was 67 years (range 58-79), 7 pts were male and 5 pts received 2 or more prior chemotherapy (range 1-4). The ORR was 0% and disease control rate was 25%. The median progression-free survival (PFS) was 0.9 months (95% CI, 0.4 to 3.0). The median overall survival was 5.8 months (95% CI, 1.1 to NR). Treatment-related G3 adverse events (hypertension, hypoalbuminemia, oral mucositis, ALT increased and creatinine increased) were observed in 4 pts. One patient with PTEN I8fs mutation had a long duration of stable disease (PFS; 6.7 months). Conclusions: This Large-scale nationwide genomic screening network was effective to identify rare targetable genetic alterations and had a potential role to develop targeted therapies in SCLC. This phase II study didn’t show promising clinical benefit of gedatolisib for advanced SCLC pts with genetic alterations in the PI3K/AKT/mTOR pathway. The safety profile of gedatolisib was similar to that reported previously. Clinical trial information: UMIN000020585.
Preliminary efficacy data of platinum-pretreated small cell lung cancer (SCLC) cohort of NCI 9881 study: A phase II study of cediranib in combination with olaparib in advanced solid tumors.
Authors: Kim Joseph W. , Hafez Navid , Soliman Hatem Hussein , Fu Siqing , Kato Shumei , Lara Primo , Vaishampayan Ulka N. , Abdul Razak Albiruni Ryan , Cardin Dana Backlund , Munster Pamela N. , Eder Joseph Paul , Swisher Elizabeth M. , Nixon Andrew B. , Patel Abhijit , Shyr Yu , Ivy S. Percy , LoRusso Patricia
Published: May 2020

9065

Background: Cediranib, a pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, suppresses expression of BRCA1, BRCA2, and RAD51 and increases sensitivity of tumors to poly-(ADP-ribose) polymerase (PARP) inhibitors in vitro. Olaparib, a PARP inhibitor, demonstrated clinical efficacy in patients with advanced solid tumors carrying a germline BRCA mutation. We therefore tested the anti-tumor activity of cediranib and olaparib combination in patients (pts) with advanced solid tumors. Here, we report the data from the SCLC cohort. Methods: This multi-institutional, two-stage, phase 2 study enrolled pts with metastatic SCLC previously treated with a minimum of one prior line of platinum-based chemotherapy in advanced setting. Patients were treated with cediranib 30mg po daily plus olaparib 200mg po BID until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by RECIST v1.1. Baseline tumor biopsies were obtained for biomarker analyses. Results: Baseline characteristics of the 25 pts enrolled are summarized below. The overall ORR rate was 28% (95% CI: 0.104,0.456). Median duration of response was 3.8 months (mos). Six of 8 pts had an objective response lasting longer than 3 mos up to 10.3 months. Disease control rate (# of pts with CR, PR or SD / # evaluable pts) was 88% (95% CI: 0.75,1.01). Median progression free survival was 4.1 mos (95% CI: 2.3, 6.2). Median OS was 5.5 mos (95% CI: 3.4, NA). Grade 3/4 adverse events (G3/4 AEs), irrespective of attribution, occurred in 14 of 25 (56%). G3/4 AEs occurring in > 10% of pts were hypertension (21%), fatigue (17%) and weight loss (13%). Conclusions: The cediranib/olaparib combination resulted in promising clinical activity with ORR of 28% in biomarker-unselected pts with platinum-pretreated SCLC. The regimen required prompt initiation of antihypertensives, but AEs were overall manageable. Analyses of mutation status in homologous recombination DNA repair genes are going and will be correlated with clinical activity. Clinical trial information: NCT02498613. [Table: see text]
The efficacy and safety profile of anlotinib with etoposide plus cisplatin/carboplatin in treatment-naive extensive-stage small cell lung cancer(SCLC) patients: Results from a phase II single-arm trial.
Authors: Deng Pengbo , Yang Huaping , Chen Cen , Hu Chengping , Cao Liming , Gu Qihua , An Jian , Li Bin , Tang Yongjun , Meng Jie , Feng Juntao
Published: May 2020

9066

Background: Combination of etoposide and cisplatin/carboplatin is the most commonly used initial chemoptherapy regiment in extensive-stage small cell lung cancer. A meta-analysis released that, there is no significant difference was observed in Objective response rate(ORR), progression-free survival (PFS), or overall survival(OS) in patients(pts) receiving cisplatin-base versus carboplatin-based regimens. We performed a single-arm phase II trial to determine if maintain of single-agent anlotinib, an oral VEGFR, FGFR, PDGFR and c-Kit tyrosine kinase inhibitor, after 4-6 cycles of anlotinib + etoposide + cisplatin/carboplatin would improve PFS and ORR. Methods: SCLC pts (18~70 yrs, extensive-stage SCLC, no prior systematic chemo/ICI therapy) received anlotinib( 12mg QD from day 1 to 14 of a 21-day cycle) +etoposide( 100mg/m2, d1~3 of 21-day cycle)+ cisplatin( 75-80mg/m2,Q3W)/ carboplatin( AUC = 5~6,Q3W) for 4~6 cycles, and anlotinib maintenance. The dual-primary endpoint were PFS and ORR. Results: Between Oct.2018 to Dec.2019, 27 pts enrolled and included in the efficacy and safety analysis: age: median 62 (range:44-71); male 93%; cisplatin/ carboplatin/ both 11%/78%/11%; 37%(10/27) of pts required chemotherapy dose modification only, and the other 30% (8/27) of pts required anlotinib+ chemotherapy dose modification.The median PFS was 9.61 months ( 95%Cl:7.80-11.42). ORR was 77.78% (21/27), disease control rate (DCR) was 96.30% (26/27).Toxicities≥grade 3 included: neutropenia 22%, leukopenia 11%, hand-foot syndrome 15%, nausea 4%, mucositis 4%, edema 4%, anorexia 4%, xerostomia 4% and fatigue 4%; there were no grade 5 toxicities. Conclusions: Combined treatment with anlotinib plus etoposide and cisplatin/carboplatin for treatment-naive extensive-stage SCLC was well tolerated with promising PFS and ORR to date but showed no new risk for AEs. Based on these encouraging results, phase III trial of anlotinib plus etoposide and cisplatin/carboplatin for treatment-naive SCLC has been warranted.
Characterization of 1,387 NSCLCs with MET exon 14 (METex14) skipping alterations (SA) and potential acquired resistance (AR) mechanisms.
Authors: Awad Mark M. , Lee Jessica Kim , Madison Russell , Classon Anthony , Kmak Jamie , Frampton Garrett M. , Alexander Brian Michael , Venstrom Jeffrey , Schrock Alexa Betzig
Published: May 2020

9511

Background: METex14 SA are oncogenic drivers in NSCLC. Due to the numerous sites around ex14 that bind the spliceosome complex, many variations can result in deleterious alterations (alts). We present a comprehensive overview of these ex14 SA across 1,387 NSCLCs and characterized potential AR mechanisms. Methods: Hybrid-capture based comprehensive genomic profiling (CGP) was performed on samples from 60,495 NSCLC patients (pts). A scoring system was applied leveraging our large database of samples with METex14 SA to optimize accurate reporting of these variants. Paired samples were collected ≥ 60 days apart (median 462). Results: 1,393 METex14 SA were identified in samples (1,278 tissue, 109 circulating tumor DNA (ctDNA)) from 1,387 NSCLC pts (2.3%) spanning multiple functional sites: donor (42%), acceptor (4.7%), poly-pyrimidine tract (15%), acceptor and polypyrimidine tract (13%), D1010 (23%), Y1003 (2.1%), and whole exon deletions (0.3%). 6 samples (5 tissue, 1 ctDNA) harbored 2 METex14 SA, each including a mutation (mut) at the donor or acceptor site. MDM2 and CDK4 amplifications (amps) co-occurred in 32% and 19% of METex14 samples, respectively, but were more common with polypyrimidine tract (37% and 23%) vs donor site (32%, p = 0.07 and 18%, p = 0.07) alts. MET co-amp was present in 12% of cases and frequency did not significantly differ by functional site. 66 (4.8%) cases (57 tissue, 9 ctDNA) had known NSCLC co-drivers, including KRAS (68%) and EGFR (14%) mut, a subset of which may represent AR. Paired samples with a METex14 SA in the 1st sample were available for 36 pts. The METex14 SA was detected in the 2nd sample for 32 pts, excluding 3 with low ctDNA. 22/36 (61%) had reportable acquired alts detected including 9 with ≥1 acquired MET muts [D1228X (4), Y1230X (3), Y1003F (1), D1228A/E/H + L1195V (1)] and 3 with acquired MET amp. Other acquired alts included ERBB2 amp and mut (1 each), EGFR ex19ins (1), KRAS amp (1), PIK3CA mut (1), AKT2 amp (1) and others with unknown functional significance. Potential AR alts were present with primary METex14 SA spanning all functional sites. Conclusions: In a dataset of > 60,000 advanced NSCLCs, METex14 SA were present in 2.3% of cases, and represented 6 major subtypes. Among paired cases, potential AR mechanisms included secondary MET alts (33%), and acquired alts in EGFR, ERBB2, KRAS, and PI3K pathways. Acquired alts were independent of the type of METex14 SA. Characterizing common co-occuring may be critical for predicting responses to MET inhibitors and informing rational combination strategies.
Amivantamab (JNJ-61186372), an anti-EGFR-MET bispecific antibody, in patients with EGFR exon 20 insertion (exon20ins)-mutated non-small cell lung cancer (NSCLC).
Authors: Park Keunchil , John Thomas , Kim Sang-We , Lee Jong Seok , Shu Catherine A. , Kim Dong-Wan , Viteri Ramirez Santiago , Spira Alexander I. , Sabari Joshua K. , Han Ji-Youn , Trigo Jose Manuel , Lee Chee Khoon , Lee Ki Hyeong , Girard Nicolas , Lorenzini Patricia A , Xie John , Roshak Amy , Thayu Meena , Knoblauch Roland Elmar , Cho Byoung Chul ,   on behalf of the CHRYSALIS Investigators
Published: May 2020

9512

Background: EGFR exon20ins-mutated NSCLC is generally refractory to EGFR tyrosine kinase inhibitors (TKIs) and is associated with poor prognosis. Amivantamab (JNJ-61186372) is a novel, fully human anti-EGFR-MET bispecific antibody whose mechanism of action can target both EGFR- and MET-driven disease and has shown monotherapy activity in patients (pts) with diverse EGFR mutant disease characterized by EGFR C797S, T790M, exon20ins, and MET amplification. We present preliminary results of pts with advanced NSCLC harboring exon20ins mutations from CHRYSALIS, an ongoing phase 1 study of amivantamab (NCT02609776). Methods: This study comprises a dose escalation phase in pts with advanced NSCLC and a dose expansion phase in pts with EGFR- and MET-mutated disease. This analysis includes all enrolled pts with exon20ins disease who received the recommended phase 2 dose (RP2D) of 1050 mg (1400 mg, pts ≥80 kg) amivantamab. Response was assessed by investigator per RECIST v1.1. Results: As of 30 Oct 2019, 50 pts with exon20ins mutations had received amivantamab at the RP2D. 39/50 pts were response-evaluable and had ≥2 disease assessments or had discontinued therapy prior to the assessment period; among these pts, 29 had prior platinum-based chemotherapy (PBCT). Median age for response-evaluable pts was 61 y (40–78), 51% were female, and median prior lines was 1 (0–7). In the 50 pts harboring exon20ins mutations treated at the RP2D, the most common adverse events (AEs) reported were rash (72%), infusion related reaction (60%), and paronychia (34%). Additional EGFR-related AEs included stomatitis (16%), pruritus (14%), and diarrhea (6%). Grade ≥3 AEs were reported in 36% of pts; 6% were treatment-related. One grade 3 diarrhea and no grade ≥3 rash was reported. Among the 39 response-evaluable pts, with a median follow-up of 4 months (1–26), the overall response rate (≥partial response [PR]) was 36% (95% CI, 21–53), and 41% (95% CI, 24–61) for the 29 pts who had prior PBCT. The clinical benefit rate (≥PR or stable disease ≥11 weeks) was 67% for response-evaluable pts and 72% for pts who had prior PBCT. Among all 14 responders, median duration of response was 10 months (1–16), with ongoing responses in 9 pts at data cutoff. Median progression-free survival was 8.3 months (95% CI, 3.0–14.8) for response-evaluable pts and 8.6 months (95% CI, 3.7–14.8) for pts who had prior PBCT. Conclusions: Amivantamab demonstrates robust and durable antitumor activity in pts with exon20ins disease, with a manageable safety profile. Clinical trial information: NCT02609776 .
Correlation of baseline molecular and clinical variables with ALK inhibitor efficacy in ALTA-1L.
Authors: Camidge D. Ross , Niu Huifeng , Kim Hye Ryun , Yang James Chih-Hsin , Ahn Myung-Ju , Li Jacky Yu-Chung , Hochmair Maximilian , Delmonte Angelo , Spira Alexander I. , Campelo Rosario Garcia , Barlesi Fabrice , Liu Geoffrey , Tiseo Marcello , Li Cong , Williams Miguel , Shin Hyunjin , Zhang Pingkuan , Popat Sanjay
Published: May 2020

9517

Background: Efficacy of ALK TKIs in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) varies. We evaluated the impact of EML4-ALK fusion variants and other baseline (BL) molecular and clinical variables on clinical efficacy of brigatinib (BRG) vs crizotinib (CRZ) as first ALK TKI therapy in pts with ALK+ NSCLC in the phase 3 ALTA-1L (NCT02737501) trial. Methods: Plasma samples were collected at screening for molecular genetic analysis of ALK and other genes implicated in NSCLC by next-generation sequencing. Exploratory analyses were performed to identify associations of clinical outcomes with oncogenic alterations including ALK fusion variants and TP53 status. Results: 124 BL samples were collected from 136 BRG-treated pts and 127 from 137 CRZ-treated pts. Pts with plasma samples were representative of the intent-to-treat population. BL ALK fusion detection rate was 52% (65/124) and 54% (68/127) in the BRG and CRZ arms, respectively, of which 83% (54/65) and 93% (63/68) were EML4-ALK fusions. In pts with detectable EML4-ALK fusions, the three predominant EML4-ALK fusion variants (V1, V2, V3) were equally distributed between arms; V1 and V3 were most prevalent (BRG/CRZ: V1, 42%/47%; V3, 42%/33%) but V1 was more frequent than V3 in pts without BL brain metastasis (47% vs 36%) or prior chemotherapy (45% vs 35%). Gender and age did not impact variant type. BRG showed higher ORR and improved mPFS vs CRZ in all variant subgroups; pts with V3 had poorer PFS compared with V1 and V2 regardless of treatment (Table). In pts with V3, BRG showed significantly improved PFS (HR=0.273, 95% CI 0.125, 0.597) and higher ORR (84% vs 67%) vs CRZ. TP53 mutation was detected in 30% (37/124) of pts in BRG arm and 26% (33/127) in CRZ arm. In pts with detectable ALK fusion, TP53 mutation showed poorer PFS in both arms than nonmutant/undetected cases (Table). BRG had better ORR and PFS vs CRZ in pts regardless of TP53 mutation status. Additional analyses of BL variables are ongoing. Conclusions: EML4-ALK fusion variant 3 and TP53 mutation were identified as poor prognosis biomarkers in ALK+ NSCLC. BRG demonstrated better efficacy than CRZ as first-line therapy in pts regardless of EML4-ALK fusion variant and TP53 mutation status. These findings may help define areas of greatest unmet need. Clinical trial information: NCT02737501 . [Table: see text]
Prevalence and association of ARID1A with driver alterations and immune checkpoint inhibitor (ICPi) biomarkers in cell-free circulating tumor DNA (ctDNA) from 27,000 non-small cell lung cancer (NSCLC) patients.
Authors: Gandara David R. , Weipert Caroline , Saam Jennifer , Riess Jonathan W. , Lenz Heinz-Josef , Kurzrock Razelle
Published: May 2020

9523

Background: Recent data suggest that the tumor suppressor gene ARID1A is associated with high anti-tumor immunity and may have value as a predictive biomarker for response to ICPi therapy in NSCLC. We examined ARID1A alterations detected in ctDNA from a large cohort of advanced NSCLC patients using a commercially available liquid biopsy assay and explored associations of ARID1A with lung cancer driver alterations and other putative ICPi mutational biomarkers. Methods: Consecutive samples from stage IIIB/IV NSCLC patients tested from March 2016 - August 2019 using a 73- to 74-gene targeted next-generation sequencing ctDNA assay (Guardant360) were queried. Testing included analysis of single nucleotide variants, insertions/deletions, fusions, and amplifications ( KEAP1 not tested). Mutation frequencies were compared using Fisher’s exact test, with variants of uncertain significance and synonymous variants excluded. Results: Of 27,776 NSCLC patients with >1 ctDNA alteration detected, 1,094 (3.9%) had >1 functional ARID1A (f ARID1A) mutation. f ARID1A mutations were significantly more common in patients with squamous histology compared to adenocarcinoma (5.1% vs 3.8%, p = 0.0007). There were significantly fewer EGFR exon 19 deletion mutations (4.9% vs 11.1%; p < 0.0001) and EGFR L858R mutations (4.0% vs 7.0%; p < 0.0001), and significantly more BRAF V600E alterations (2.2% vs 1.4%; p = 0.0338) in patients with f ARID1A. There was no significant difference in the frequency of ALK and ROS1 fusions, nor STK11 mutations between patients with and without f ARID1A (8.0% vs 6.8%; p = 0.126). Activating KRAS mutations were significantly more frequent in patients with f ARID1A (31.1% vs 19.4%; p < 0.0001), including KRAS G12C (10.9% vs 7.0%; p < 0.0001). Conclusions: These data provide a mutational landscape for f ARID1A mutations in NSCLC. f ARID1A was associated with significant differences in the frequency of multiple lung cancer driver alterations, of particular interest in the EGFR-mutated cohort, where ICPi efficacy is low. The frequency of STK11 mutations, a possible negative predictor of ICPi efficacy, was not significantly different. KRAS mutations were significantly more frequent in patients with f ARID1A, notable given recent data reporting that KRAS mutations, particularly KRAS G12C, may be a positive predictor of ICPi response in NSCLC. Determination of ICPi efficacy in patients with f ARID1A is in-process.