bluuebunny/crossref_metadata_2025 huggingface dataset:
Updates from ICARIA-MM, a phase 3 study of isatuximab (Isa) plus pomalidomide and low-dose dexamethasone (Pd) versus Pd in relapsed and refractory multiple myeloma (RRMM).
Authors: Richardson Paul G. , Perrot Aurore , F. San-Miguel Jesús , Beksac Meral , Spicka Ivan , Leleu Xavier , Schjesvold Fredrik , Moreau Philippe , Dimopoulos Meletios A. , Huang Jeffrey SY. , Minarik Jiri , Cavo Michele , Prince H. Miles , Zheng Cheng , Dubin Franck , Van De Velde Helgi , Anderson Kenneth Carl
Published: June 2021

8017

Background: Isa is an approved monoclonal antibody that binds to a specific epitope on the CD38 receptor. The Phase 3 ICARIA-MM study (NCT02990338) demonstrated significantly improved progression-free survival (PFS) with Isa-Pd vs Pd ( P= 0.001) and a manageable safety profile (Attal M, et al. Lancet 2019;394:2096-2107). Here we report updated ICARIA results. Methods: Pts with RRMM (N = 307) who have received ≥2 prior therapies, including lenalidomide (Len) and a proteasome inhibitor (PI), were randomized to Isa-Pd (n = 154) or Pd (n = 153). Isa was administered intravenously at 10 mg/kg weekly for 4 weeks, and every other week thereafter. This preplanned second interim analysis assessed longer term outcomes, including time to next treatment (TTNT), overall survival (OS), time from randomization to disease progression on first subsequent therapy or death (PFS2), and safety. Results: Pts had a median of 3 prior lines of therapy (IQR 2–4; table). As of Oct 1, 2020 (median follow-up, 35.3 months [mo]), 27 Isa-Pd pts (18%) vs 12 Pd pts (8%) were still on treatment; 60% vs 72% had proceeded to subsequent therapy. Median TTNT was 15.5 mo with Isa-Pd vs 8.9 mo with Pd (hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.42–0.74; P< 0.0001); 24% vs 58% of pts with subsequent therapy received daratumumab (dara). Overall response rate (ORR) in subsequent treatment with dara monotherapy was higher after Pd (38%) than Isa-Pd (14%), but was similar (32% vs 31%) with dara combination therapy (table). Median PFS2 in the intent-to-treat population was 17.5 mo with Isa-Pd vs 12.9 mo with Pd (HR 0.76; 95% CI 0.58–0.99; P= 0.0202). Median OS was 24.6 mo with Isa-Pd vs 17.7 mo with Pd (HR 0.76; 95% CI 0.58–1.01; one-sided P= 0.0280). Median treatment duration was 47.6 weeks (range 1.3–171.6) with Isa-Pd vs 24.0 weeks (range 1.0–168.6) with Pd. Serious treatment-emergent adverse event (TEAEs) were seen in 73% of Isa-Pd pts vs 60% of Pd pts. Most frequent non-hematologic TEAEs (any grade) with Isa-Pd were infusion reaction (38%), upper respiratory tract infection (34%), and diarrhea (30%). Grade 3–4 neutropenia (85% vs 71%) and thrombocytopenia (34% vs 25%) were more frequent with Isa-Pd than with Pd. Conclusions: Isa-Pd demonstrates a significant improvement in TTNT and PFS2 compared with Pd. A strong trend in OS benefit was also seen in the Isa-Pd arm, with approximately 7 mo improvement in median OS. The overall safety profile remains unchanged from prior analyses. Funding: Sanofi. Clinical trial information: NCT02990338. [Table: see text]
Updated overall survival (OS) and exploratory analysis from the randomized, phase II EVAN study of erlotinib (E) versus vinorelbine plus cisplatin (NP) as adjuvant therapy in Chinese patients with stage IIIA EGFR+ NSCLC.
Authors: Yue Dongsheng , Xu Shi-Dong , Wang Qun , Li Xiaofei , Shen Yi , Zhao Heng , Chen Chun , Mao Weimin , Liu Wei , Liu Junfeng , Zhang Lan-Jun , Ma Haitao , Li Qiang , Yang Yue , Liu Yongyu , Chen Haiquan , Zhang Zhenfa , Zhang Bin , Gong Fuyu , Wang Changli
Published: June 2021

8520

Background: The EVAN study of E vs NP in stage III EGFR+ NSCLC has met its primary endpoint and been previously published: 2-year disease-free survival was 81.4% (95% CI, 69.6–93.1) in E group vs 44.6% (95% CI, 26.9-62.4) in NP group (HR, 1.823; 95% CI, 1.194–2.784; P=0.0054). We report 5-year OS and exploratory results from EVAN with a further 43 month follow up (cutoff date: Jan 6, 2021). Methods: Patients with stage IIIA EGFR+ NSCLC were randomized assigned (1:1) into either E arm (n=51, 150mg/day) or NP arm (n=51, vinorelbine 25mg/m2 on day 1, 8 and cisplatin 75mg/m2 on day 1 of a 21-day cycle). In order to explore the relationship between patient benefits and co-occurring variants, 47 patients received whole exome sequencing (WES) analysis (E, n=24; NP, n=23). Results: Median follow-up time was 54.8 months for E and 63.9 months for NP. E improved OS and 5-year survival rate compared with NP in ITT population. The median OS was 84.2m (95% CI, 78.1,-) with E vs 61.1m (95% CI, 39.6-82.1) with NP (HR, 0.318; 95% CI, 0.151-0.670). The 5-year survival rates were 84.8% (95%CI, 72.0-97.6) and 51.1% (95% CI, 34.7-67.5), respectively. In the WES analysis, we found that the most frequent genes with co-occurring variants at baseline were TP53, MUC16, FAM104B, KMT5A and DNAH9, and additional EGFR variants, each with similar prevalence regardless of EGFR-activating mutation subgroup. Moreover, in the erlotinib-treated patients, the SNP mutation of UBXN11 was associated with significantly worse DFS (P=0.0111). Conclusions: This is the first randomized study of EGFR-TKI to demonstrate a clinically meaningful improvement in OS vs chemotherapy in stage III EGFR+ NSCLC (5-year survival rate 84.8% in E vs 51.1% in NP). The co-occurring variants at baseline may be associated with reduced DFS. Further studies are required to confirm our results (EVAN, NCT01683175). Clinical trial information: NCT01683175.
Deep learning to predict subtypes of poorly differentiated lung cancer from biopsy whole slide images.
Authors: Toyokawa Gouji , Kanavati Fahdi , Momosaki Seiya , Tateishi Kengo , Takeoka Hiroaki , Okamoto Masaki , Yamazaki Koji , Takeo Sadanori , Iizuka Osamu , Tsuneki Masayuki
Published: June 2021

8536

Background: Lung cancer is the leading cause of cancer-related death in many countries, and its prognosis remains unsatisfactory. Since treatment approaches differ substantially based on the subtype, such as adenocarcinoma (ADC), squamous cell carcinoma (SCC) and small cell lung cancer (SCLC), an accurate histopathological diagnosis is of great importance. However, if the specimen is solely composed of poorly differentiated cancer cells, distinguishing between histological subtypes can be difficult. The present study developed a deep learning model to classify lung cancer subtypes from whole slide images (WSIs) of transbronchial lung biopsy (TBLB) specimens, in particular with the aim of using this model to evaluate a challenging test set of indeterminate cases. Methods: Our deep learning model consisted of two separately trained components: a convolutional neural network tile classifier and a recurrent neural network tile aggregator for the WSI diagnosis. We used a training set consisting of 638 WSIs of TBLB specimens to train a deep learning model to classify lung cancer subtypes (ADC, SCC and SCLC) and non-neoplastic lesions. The training set consisted of 593 WSIs for which the diagnosis had been determined by pathologists based on the visual inspection of Hematoxylin-Eosin (HE) slides and of 45 WSIs of indeterminate cases (64 ADCs and 19 SCCs). We then evaluated the models using five independent test sets. For each test set, we computed the receiver operator curve (ROC) area under the curve (AUC). Results: We applied the model to an indeterminate test set of WSIs obtained from TBLB specimens that pathologists had not been able to conclusively diagnose by examining the HE-stained specimens alone. Overall, the model achieved ROC AUCs of 0.993 (confidence interval [CI] 0.971-1.0) and 0.996 (0.981-1.0) for ADC and SCC, respectively. We further evaluated the model using five independent test sets consisting of both TBLB and surgically resected lung specimens (combined total of 2490 WSIs) and obtained highly promising results with ROC AUCs ranging from 0.94 to 0.99. Conclusions: In this study, we demonstrated that a deep learning model could be trained to predict lung cancer subtypes in indeterminate TBLB specimens. The extremely promising results obtained show that if deployed in clinical practice, a deep learning model that is capable of aiding pathologists in diagnosing indeterminate cases would be extremely beneficial as it would allow a diagnosis to be obtained sooner and reduce costs that would result from further investigations.
Analysis of homologous recombination DNA repair gene mutation status in patients with metastatic small cell lung cancer treated with cediranib and olaparib on NCI 9881 study.
Authors: Kim Joseph W. , Radke Marc R. , Hafez Navid , Soliman Hatem Hussein , Fu Siqing , Kato Shumei , Lara Primo "Lucky" N. , Vaishampayan Ulka N. , Abdul Razak Albiruni Ryan , Cardin Dana Backlund , Munster Pamela N. , Eder Joseph Paul , Shyr Yu , Ivy S. Percy , LoRusso Patricia , Swisher Elizabeth M.
Published: June 2021

8563

Background: Cediranib, a pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, suppresses expression of homologous recombination DNA repair (HRR) genes and increases sensitivity of tumors to a poly-(ADP-ribose) polymerase (PARP) inhibitor in vitro and in vivo models of breast and ovarian cancer. Olaparib, a PARP inhibitor, demonstrated clinical efficacy in patients with advanced solid tumor with a deleterious mutation in HRR genes. We hypothesized that cediranib induces HRR deficient phenotype by suppressing expression of HRR genes and cediranib and olaparib combination (C+O) results in an objectives response in patients with HRR proficient (HRP) advanced solid tumors. Herein, we report the biomarker data from analyses of targeted sequencing of 84 DNA repair (DR) genes with BROCA-HR assay in patients with metastatic small cell lung cancer (mSCLC). Methods: This multi-institutional phase 2 trial enrolled patients with mSCLC previously treated with a platinum-based chemotherapy. Patients received cediranib 30mg orally (po) daily plus olaparib 200mg po twice daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by RECIST v1.1. A tumor biopsy was obtained from the patients with safely accessible metastatic tumor. HRR deficiency (HRD) was defined as presence of a deleterious mutation in any of the 10 key HRR-related genes per BROCA-HR assay including: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12 (somatic mutations only), NBN, PALB2, RAD51C, or RAD51D. Otherwise, the tumors were defined as HRR proficiency (HRP). Results: A total of 25 patients with SCLC received the study treatment. Fourteen patients had available tumor biopsy samples and/or germline available for BROCA-HR. One patient (7%) was determined to have a HRD tumor by a presence of PALB2 mutation. This patient had stable disease as a best overall response but came off study due to unequivocal clinical progression. Thirteen patients (93%) had a HRP tumor. Six of these (46%) patients had PR. Median PFS in patients with HPR tumors was 122 days. The most common gene alterations detected by BROCA-HR assay was TP53 (93%) and RB1 (79%). Other DR gene alterations noted from our study samples were MRE11, CKD12 PALB2, ERCC4, FANCB, and BAP1. Conclusions: HRD was infrequent in our mSCLC samples. C+O resulted in objective responses in 46% of mSCLC patients with HRP tumors. Mutations in TP53 and RB1 were the most common gene alterations. Further investigation in warranted to confirm this observation. Clinical trial information: NCT02498613.
Combination of quantitative features from H&E biopsies and CT scans predicts response to chemotherapy and overall survival in small cell lung cancer (SCLC).
Authors: Barrera Cristian , Khorrami Mohammadhadi , Jain Prantesh , Fu Pingfu , Butler Kate , Osme Abdullah , Toro Paula , Viswanathan Vidya Sankar , Chahar Satyapal , Dowlati Afshin , Madabhushi Anant
Published: June 2021

8572

Background: Small Cell Lung Cancer (SCLC) is an aggressive malignancy with a rapid growth, and Chemotherapy remains mainstay of treatment. Identifying therapeutic targets in SCLC presents a challenge, partially due to a lack of accurate and consistently predictive biomarkers. In this study we sought to evaluate the utility of a combination of computer-extracted radiographic and pathology features from pretreatment baseline CT and H&E biopsy images to predict sensitivity to platinum-based chemotherapy and overall survival (OS) in SCLC. Methods: Seventy-eight patients with extensive and limited-stage SCLC who received platinum-doublet chemotherapy were selected. Objective response to chemotherapy (RECIST criteria) and overall survival (OS) as clinical endpoints were available for 51 and 78 patients respectively. The patients were divided randomly into two sets (Training (Sd), Validation (Sv)) with a constraint (equal number of responders and nonresponders in Sd)—Sd comprised twenty-one patients with SCLC. Sv included thirty patients. CT scans and digitized Hematoxylin Eosin-stained (H&E) biopsy images were acquired for each patient. A set of CT derived (46%) and tissue derived (53%) image features were captured. These included shape and textural patterns of the tumoral and peritumoral regions from CT scans and of tumor regions on H&E images. A random forest feature selection and linear regression model were used to identify the most predictive CT and H&E derived image features associated with chemotherapy response from Sd. A Cox proportional hazard regression model was used with these features to compute a risk score for each patients in Sd. Patients in Sv were stratified into high and low-risk groups based on the median risk score. Kaplan-Meier survival analysis was used to assess the prognostic ability of the risk score on Sv. Results: The risk score comprised nine CT (intra and peri-tumoral texture) and six H&E derived (cancer cell texture and shape) features. A linear regression model in conjunction with these 15 features was significantly associated with chemo-sensitivity in Sv (AUC = 0.76, PRC = 0.81). A multivariable model with these 15 features was significantly associated with OS in Sv (HR = 2.5, 95% CI: 1.3-4.9, P = 0.0043). Kaplan-Meier survival analysis revealed a significantly reduced OS in the high-risk group compared to the low-risk group. Conclusions: A combined CT and H&E tissue derived image signature model predicted response to chemotherapy and improved OS in SCLC patients. Image features from baseline CT scans and H&E tissue slide images may help in better risk stratification of SCLC patients. Additional independent validation of these quantitative image-based biomarkers is warranted.
Myasthenia gravis-associated thymoma and myasthenia gravis-free thymoma have distinct somatic mutation and gene expression profiles.
Authors: Zhang Yi , Li Xiaomo , Lu Gaojun , Ma Tonghui , Shi Kejian
Published: June 2021

8573

Background: A significant proportion of thymoma patients have concurring autoimmune diseases such as myasthenia gravis (MG). However, the molecular signature of myasthenia gravis-associated thymoma (MGT) is largely unknown. Genomic and transcriptomic profiling of MGT may provide valuable insight to the etiology of MGT and facilitate the development of effective therapeutic approaches. Methods: To study the molecular signature of MGT, 26 thymoma patients were divided into two subgroups according to their clinical presentations. One group included 16 thymoma patients associated with MG (MGT) and the other group had 10 patients without MG (MGF). We profiled the genomic and transcriptomic changes of tumor samples from both subgroups with whole exome sequencing (WES) and RNA sequencing (RNA-seq). Results: The WES results indicated that more genes were mutated in the MGF subgroup than the MGT group, although the difference between two subgroups was not statistically significant. There were only five mutated genes ( NBPF1, HRAS, ATAD3B, IFITM3 and MUC4) appeared total mutation frequency exceeded 10%. NBPF1 is the most frequently mutated gene, seen in 25% of the MGTs (4/16) and 10% (1/10) of the MGFs. Neuroblastoma breakpoint family member 1 encoded by NBPF1 was involved in several cancer types including gastric cancer and neuroblastoma, but there is no report on the link of NBPF1 with thymoma or MG. Recent studies showed that NBPF1 is a negative regulator of Akt-p53-Cyclin D and PI3K/mTOR signal pathways. Recurrent mutations in HRAS was only observed in MGFs but not MGTs. Genes mutated in more than one patient were NBPF1, ATAD3B, RPDM9, LOC642131, ADAM21, CGNL1, MUC4 and MUC2 in the MGT subgroup, while only three genes HRAS, CSPG4 and IFITM3 were mutated in more than one patient in the MGF subgroup. Moreover, RNA-seq data identified 106 significantly differentially expressed genes, including 54 upregulated and 52 downregulated genes in the MGT subgroup, further pathway enrichment analysis revealed that the Hippo, Wnt, TGF‐β and focal adhesion signaling pathways were significantly downregulated in the MGT subgroup compared with the MGF subgroup. Conclusions: Our findings provide new insights for the etiology of thymoma with and without MG. mTOR signaling pathway is a key regulator of immune response. Importantly, the protein level of some components in the mTOR pathway was reduced in MG caused-atrophic muscle. Further investigation is warranted to examine the functional roles of NBPF1 in mTOR signaling regulation and the etiology of MG-associated thymoma.
Preliminary safety and efficacy results from phase 1 studies of DZD9008 in NSCLC patients with EGFR Exon20 insertion mutations.
Authors: Yang James Chih-Hsin , Wang Mengzhao , Mitchell Paul , Fang Jian , Nian Weiqi , Chiu Chao-Hua , Zhou Jianying , Zhao Yanqiu , Su Wu-Chou , Camidge D. Ross , Yang Tsung-Ying , Zhu Viola Weijia , Millward Michael , Fan Yun , Huang Wen Tsung , Cheng Ying , Jiang Liyan , Zheng Li , Ye Xiuhui , Janne Pasi A.
Published: June 2021

9008

Background: There are no approved targeted therapies for EGFR exon20 insertion (exon20ins) mutant NSCLC. DZD9008 is a rationally designed selective, irreversible EGFR exon20ins inhibitor being studied in two ongoing phase 1/2 studies (NCT03974022 and CTR20192097). Methods: The objectives of the studies are to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor efficacy of DZD9008 in NSCLC with EGFR or HER2 mutations. Both studies include dose escalation and expansion cohorts. Pooled analysis is applied to define recommended phase 2 dose (RP2D). Results: Between July 9, 2019 and February 5, 2021, 97 NSCLC patients with EGFR or HER2 mutations were dosed with DZD9008 (dose range: 50 mg to 400 mg, once daily). M/F: 44/53; 59 with EGFR exon 20. DZD9008 was well tolerated up to 400 mg (MTD) once daily. The DLTs were diarrhea and cardiac arrhythmia. The most common TEAEs were diarrhea (grade 3, 5.2%) and skin rash (grade 3, 1%). DZD9008 showed approximately dose-proportional PK, with a half-life of around 50 hours. Fifty-six patients with > 16 different EGFR exon20ins mutations had > 1 post-treatment efficacy assessment. Prior therapies: median 2 (range 1 - 10), prior chemotherapy 92.9% (52/); prior TKI 44.6% (25/56) including 1 patient had poziotinib treatment; 42.9% (24/56) with brain metastasis. Partial response was observed at ≥ 100 mg dose levels. At the RP2D dose of 300 mg once daily, the objective response rate was 48.4% (15/31), and disease control rate (DCR) was 90.3% (28/31). Responses were observed in 2 patients with prior JNJ-61186372 treatment. Anti-tumor activity was observed across different EGFR exon20ins mutation subtypes. By data cut-off, the median treatment duration was 100 days (range 1 – 422). The longest duration of response was over 6 months, and 18 out of 22 responders are still responding. Conclusions: DZD9008 showed a favorable safety profile and promising anti-tumor efficacy in pre-treated NSCLC with EGFR exon20ins mutations. The updated data will be presented at the meeting. DZD9008 is currently in phase II clinical development (NCT03974022). Clinical trial information: NCT03974022.
Nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for advanced non-small cell lung cancer (NSCLC): 4-year update from CheckMate 227.
Authors: Paz-Ares Luis G. , Ciuleanu Tudor-Eliade , Lee Jong-Seok , Urban Laszlo , Bernabe Caro Reyes , Park Keunchil , Sakai Hiroshi , Ohe Yuichiro , Nishio Makoto , Pluzanski Adam , Ramalingam Suresh S. , Brahmer Julie R. , Borghaei Hossein , O'Byrne Kenneth John , Hellmann Matthew D. , Memaj Arteid , Bushong Judith , Tran Phuong , Reck Martin
Published: June 2021

9016

Background: 1L NIVO + IPI was shown to provide durable long-term overall survival (OS) benefit vs chemo regardless of tumor programmed death ligand 1 (PD-L1) expression in patients (pts) with advanced NSCLC in CheckMate 227 Part 1 (NCT02477826); 3-year OS rates were 33% vs 22% in pts with PD-L1 ≥ 1% (HR, 0.79 [95% CI, 0.67–0.93]) and 34% vs 15% in pts with PD-L1 < 1% (HR, 0.64 [95% CI, 0.51–0.81]). Here we report updated results from the study with 4 years’ minimum follow-up. Methods: Adults with previously untreated stage IV / recurrent NSCLC, no known EGFR/ ALK alterations , and ECOG performance status ≤ 1 were enrolled; pts were stratified by squamous (SQ) and non-squamous (NSQ) histology. Pts with PD-L1 ≥ 1% (n = 1189) were randomized 1:1:1 to receive NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), NIVO alone (240 mg Q2W), or chemo. Pts with PD-L1 < 1% (n = 550) were randomized 1:1:1 to receive NIVO + IPI, NIVO (360 mg Q3W) + chemo, or chemo. OS with NIVO + IPI vs chemo in pts with PD-L1 ≥ 1% was the primary endpoint. Results: With minimum follow-up of 49.4 months (database lock, Feb 18, 2021), pts were at least 2 years beyond the protocol-specified end of immunotherapy treatment. Pts with PD-L1 ≥ 1% continued to show durable benefit with NIVO + IPI vs chemo (HR, 0.76 [95% CI, 0.65–0.90]); 4-year OS rates were 29% (NIVO + IPI), 21% (NIVO), and 18% (chemo). At 4 years, 14% (NIVO + IPI), 10% (NIVO), and 4% (chemo) remained progression free. Among responders, 34%, 30%, and 7% remained in response, respectively. In an exploratory analysis in pts with PD-L1 ≥ 50%, 4-year OS rates were 37% (NIVO + IPI), 26% (NIVO), and 20% (chemo). In pts with PD-L1 < 1%, OS HR for NIVO + IPI vs chemo was 0.64 (95% CI, 0.51–0.81); 4-year OS rates were 24% (NIVO + IPI), 13% (NIVO + chemo) and 10% (chemo). At 4 years, 12% (NIVO + IPI), 7% (NIVO + chemo), and 0% (chemo) remained progression free. Among responders, 31%, 13%, and 0% remained in response, respectively. Among pts who progressed on NIVO + IPI vs chemo, 7% vs 40% (PD-L1 ≥ 1%), and 9% vs 33% (PD-L1 < 1%), received subsequent immunotherapy. Benefit with NIVO + IPI vs chemo was observed for both SQ and NSQ histology (Table). With long-term follow-up, no new safety signals were identified. Conclusions: With 4 years’ minimum follow-up, 1L NIVO + IPI continued to provide durable, long-term OS benefit vs chemo in pts with advanced NSCLC regardless of PD-L1 expression or histology. Clinical trial information: NCT02477826. [Table: see text]
Whole-exome sequencing in advanced-stage sensitizing EGFR mutation non-small cell lung cancer: Explore resistance biomarkers to EGFR TKI treatment.
Authors: Vinayanuwattikun Chanida , Sitthideatphaiboon Piyada , Teerapakpinyo Chinachote , Korphaisarn Krittiya , Poungvarin Naravat , Chantranuwatana Poonchavist , Shuangshoti Shanop , Aporntewan Chatchawit , Sriuranpong Virote
Published: June 2021

9039

Background: Despite the development of predictive biomarkers to shape treatment paradigms and outcomes, 10-20% of de novo EGFR TKI resistance advanced non-small cell lung cancer (NSCLC) in the presence of EGFR mutation remains the issue of concern. Methods: We explored clinical factors in 332 advanced NSCLC who received EGFR TKI and molecular characteristics through 65 whole exome sequencing of various EGFR TKI responses including; de novo (progression within 3 months), intermediate response (IRs) and long-term response (LTRs) (durability > 2 year). Results: Uncommon EGFR mutation subtype was a significant variable in de novo resistance vs. IRs and LTRs with odd ratios of 6.83 ([95% CI 2.36 – 19.80], p-value < 0.001) and 16.84 ([95%CI 1.66 – 171.45, p-value 0.02), respectively. The remaining sensitizing EGFR mutation subtype (exon 19 del and L858R) accounted for 75% of de novo resistance. Genomic landscape analysis was conducted, focusing in 10 frequent oncogenic signaling pathways with functional contributions; cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGF-β, p53 and β-catenin/Wnt signaling. Cell cycle pathway was the only significant alteration pathway among groups with the FDR p-value of 6×10-4. We found only significant q-values of < 0.05 in 7 gene alterations; CDK6, CCNE1, CDK4, CCND3, MET, FGFR4 and HRAS which enrich in de novo resistance [range 36-73%] compared to IRs/LTRs [range 4-22%]. Amplification of CDK4/6 was significant in de novo resistance, contrary to IRs and LTRs (91%, 27.9% and 0%, respectively). The presence of co-occurrence CDK4 /6 amplification correlated with poor disease outcome with HR of progression-free survival of 3.63 [95% CI 1.80-7.31, p-value < 0.001]. Conclusions: The presence of CDK4 /6 amplification in pretreatment specimen serve as a predictive biomarker for de novo resistance in sensitizing EGFR mutation.
Features in genomics and tumor immune microenvironment in NSCLC treated with neoadjuvant PD-1 blockade.
Authors: Wang Shuhang , Li Ning , Mao Beibei , Ying Jianming , Tao Xiuli , Tang Wei , Zhang Lei , Geng Xiao , Zhang Fan , Xue Qi , Wu Lijia , Zhang Henghui , Gao Shugeng , He Jie
Published: June 2021

9063

Background: Results from several clinical trials have preliminarily demonstrated the safety and effectiveness of single PD-1 inhibitors in neoadjuvant setting for resectable non-small cell lung cancer (NSCLC). However, only around 40% patients could achieve Major Pathological Response. How to select patients who could benefit from single PD-1 blockade remains elusive. Methods: In this study, we aimed to assess the association of PD-L1 expression, tumor mutation burden (TMB), copy number alteration (CNA, including copy number gain and loss) burden with the pathological response to neoadjuvant PD-1 blockade. We also evaluated the dynamic changes of tumor immune microenvironment (TIME) by analyzing pre-immunotherapy treatment tumor biopsy samples from twenty-nine NSCLC patients as well as the matched post-surgery samples after neoadjuvant sintilimab treatment and resection. Targeted DNA sequencing (543 genes), PD-L1 immunochemistry staining (22C3) and multiplex immunofluorescence (CD4, CD8, CD9) were applied. Results: The degree of pathological regression and major pathological response (MPR), were positively correlated with tumor proportion score (TPS) of PD-L1 (R = 0.40, p = 0.04) and negatively correlated with copy number gain (CNgain) burden (R = -0.44, p = 0.04). Of note, the combination of CNgain burden and TPS can better stratify MPR patients compared to CNgain or TPS alone. Whereas, TMB only had a marginal association with pathological response (R = 0.32, p = 0.15). Additionally, PD-1 blockade led to an increase in CD8+PD-1-T cells in the tumor region (p = 0.04, Mann-Whitney U test for paired samples) and a reduction in Tregs and M2 macrophages in the stromal region (p < 0.05, Mann-Whitney U test for paired samples). Further investigation showed that the degree of CD8+PD-1-T cell increase was significantly associated with MPR (p < 0.05, Mann-Whitney U test). Intriguingly, we also observed a substantial reduction in CD19+ cells in the non-MPR group but not in the MPR group, indicating the involvement of B cells in improving neoadjuvant immunotherapy response in NSCLC patients. Conclusions: TPS and CNgain burden were correlated with pathological response to neoadjuvant immunotherapy in NSCLC patients. This may provide potential selective indicators for future clinical trials of neoadjuvant immunotherapy. The dynamic changes of components in the tumor immune microenvironment may provide novel insight into the immune responses induced by neoadjuvant PD-1 blockade therapy.
Association between improvements in survival of metastatic NSCLC patients and targeted- and immuno-therapy.
Authors: Ramagopalan Sreeram , Leahy Thomas P. , Ray Joshua , Wilkinson Samantha , Sammon Cormac J. , Subbiah Vivek
Published: June 2021

9090

Background: Significant improvements in mortality among NSCLC cancer patients in the US over the past two decades have recently been reported based on SEER data. The timing of these improvements led to suggestions that they are primarily a result of the introduction of new and innovative treatments, however few studies have directly investigated this. Methods: We utilised the US Flatiron Health database to identify a cohort of non-biomarker (EGFR/ALK/ROS1/BRAF) positive metastatic NSCLC (mNSCLC) patients and a separate cohort of ALK positive (ALK+) patients diagnosed between 2012 and 2019. Multivariable Cox models adjusting for baseline characteristics and receipt of targeted and immunotherapy were utilised to explore the relationship between these variables and changes in the hazard of death by calendar year in each cohort. Results: We identified cohorts of 30,076 (54.7% Males) non-biomarker positive and 652 (45.4% males) ALK+ mNSCLC cancer patients in the database eligible for the analysis. Survival in both cohorts improved over time. After adjustment for differences in baseline characteristics the hazard of death in non-biomarker positive patients diagnosed in 2015, 2016, 2017, 2018 and 2019 was observed to be 14%, 13%, 16% 19% and 21% lower respectively than that in those diagnosed in 2012. Upon additionally adjusting for receipt of first line or second line immunotherapy the decrease in the hazard of death by calendar year was no longer observed, suggesting improvements in survival observed over time may be explained by the introduction of these innovative treatments. Similarly, decreases in the hazard of death were only observed in ALK+ patients diagnosed in 2018 and 2019 relative to 2012 and were no longer observed following adjustment for the use of ALK inhibitors. Conclusions: Our findings expand on the SEER data and provide direct evidence linking improvements in survival of NSCLC patients over the past decade with the introduction of innovative therapies.[Table: see text]
RATIONALE-307: Tislelizumab plus chemotherapy versus chemotherapy alone as first-line treatment for advanced squamous NSCLC in patients aged ≥ 65.
Authors: Wang Jie , Lu Shun , Yu Xinmin , Hu Yanping , Sun Yuping , Wang Zhijie , Zhao Jun , Yu Yan , Hu Chunhong , Yang Kunyu , Feng Guosheng , Ying Kejing , Zhuang Wu , Zhou Jianying , Wu Jingxun , Leaw Shiang Jiin , Zhang Jing , Lin Xiao , Yang Nong
Published: June 2021

9102

Background: Tislelizumab is a humanized, monoclonal antibody with high affinity and specificity for the programmed cell death protein 1 (PD-1). It has demonstrated antitumor activity in advanced lung cancers. We conducted a Phase 3, multicenter, randomized open-label study (NCT03594747) to assess the safety and efficacy of tislelizumab plus chemotherapy in patients (pts) with advanced squamous NSCLC. As previously reported, tislelizumab (TIS) significantly improved progression free survival (PFS) and reduced the risk of progression. Here, we report results from a sub-group of pts aged ≥ 65 years. Methods: Eligible pts (aged 18-75 years) enrolled in China were treatment-naive for locally advanced or metastatic squamous NSCLC. Pts were stratified by disease stage (IIIB vs IV), and programmed death-ligand 1 (PD-L1) expression (<1% vs 1-49% vs 50% tumor cells), and randomized 1:1:1 to Arm A: TIS 200 mg + paclitaxel (P) 175 mg/m2 and carboplatin (C) area under the plasma concentration 5 (every 3 weeks [Q3W] on day 1); Arm B: TIS + nab-paclitaxel ( nab-P) 100 mg/m2 (Q3W on days 1, 8 and 15) + C (Q3W on Day 1); or Arm C: P + C (Q3W on day 1). P, nab-P and C were administered for 4 to 6 cycles. TIS was administered until loss of benefit, withdrawal of consent or start of a new anticancer therapy. In this sub-group analysis, pts aged ≥ 65 years were evaluated according to the primary endpoint (PFS) and key secondary endpoints (objective response rate and safety). Results: Overall, 127 pts aged ≥ 65 years were randomized to receive treatment. Median age of pts aged ≥ 65 was 68.0 years and 120 pts (94.5%) were male. In total, 18 (46.2%), 20 (38.5%), and 34 (94.4%) pts in Arms A, B and C, respectively, had discontinued treatment. In Arm C 22/34 pts had completed chemotherapy. The primary and secondary endpoints, PFS and ORR, were longer and higher, respectively, in Arms A and B, compared with Arm C (Table). Grade ≥ 3 treatment related adverse events (TRAEs) occurred in 33 (84.6%), 44 (84.6%) and 28 (82.4%) pts aged ≥ 65 years in Arms A, B and C, respectively, compared with 103 (85.8%), 99 (83.9%) and 94 (80.3%) pts aged ≥ 18 years enrolled in the study. The most commonly reported TRAEs in pts aged ≥ 65 years were anemia, decrease in neutrophil count, and alopecia. Conclusions: In this sub-group analysis, PFS and ORR were longer and higher, respectively, with TIS in pts aged ≥ 65 years with advanced squamous NSCLC. The safety profile of TIS in pts aged ≥ 65 years was similar to the safety profile for all aged pts aged ≥ 18 years. Clinical trial information: NCT03594747. [Table: see text]
Patterns of survival in NSCLC with de novo brain metastasis: SRS, WBRT, and no radiotherapy cohorts.
Authors: Saravia Diana , Bilani Nadeem , Elson Leah , Elimimian Elizabeth Blessing , Alley Evan W. , Naik Mihir , Nahleh Zeina A. , Arteta-Bulos Rafael
Published: June 2021

9122

Background: Prognostic determinants in metastatic non-small cell lung cancer (mNSCLC) include numerous sociodemographic and clinical characteristics. We provide granular, real-world survival data in different cohorts of this heterogeneous population, stratifying by: age, Charlson/Deyo scoring (CDS) of comorbidity, tumor histology, and use of immunotherapy. Methods: This retrospective analysis uses the National Cancer Database (NCDB) to explore patterns of survival in patients diagnosed between 2010-2016 with mNSCLC involving the brain. Kaplan-Meier (KM) modeling was used to evaluate for differences in overall survival (OS) between 3 cohorts of patients: those undergoing 1) stereotactic radiosurgery (SRS), 2) whole-brain radiotherapy (WBRT), and 3) those not undergoing brain radiotherapy (NR) as part of the first course of treatment. As per Table, we ran 8 KM models to generate median OS (mOS) data across stratifications for age (<70 vs. ≥70), CDS (0-1 vs. 2-3), tumor histology (adenocarcinoma vs. squamous), and use of immunotherapy (yes vs. no). We provide a ranked order of these 3 cohorts by mOS (‘survival sequence’, or ‘SS’), as well as differences in mOS (‘ΔmOS’) between NR and WBRT – the two cohorts most comparable in life expectancy. Results: A total of n=38,119 patients were included in this study. Most received WBRT (n=18,052, 47.4%), n=6,562 (17.2%) received SRS, while n=13,505 (35.4%) did not receive brain radiation as part of their first course of treatment. In all subgroups, patients treated with SRS for brain metastasis had the highest mOS. Survival for those receiving WBRT was better or comparable (difference in mOS <0.5 months) to those that did not receive radiotherapy, except in patients aged ≥70 (SS: NR > WBRT; KM p-value <0.05; ΔmOS of 1.6 months), those with Charlson-Deyo comorbidity scores of 2-3 (SS: NR > WBRT; KM p-value <0.05; ΔmOS: 0.6 months), those with squamous carcinoma (SS: NR > WBRT; KM p-value <0.05; ΔmOS: 0.7 months), and those already receiving immunotherapy (SS: NR > WBRT; KM p-value <0.05; ΔmOS: 0.6 months). Conclusions: SRS for de novo brain metastases is associated with improved OS in mNSCLC. In contrast, the burden of WBRT may outweigh the survival benefit it affords in patients ≥70, and those with comorbidities. Squamous cell carcinomas may be associated with more radio-resistance than adenocarcinomas to WBRT. Finally, as previously described in melanoma, the survival benefit afforded by brain radiotherapy may be lower in patients on immunotherapy.[Table: see text]
Effects of baseline lactate dehydrogenase (LDH), interferon gamma (IFN-g) expression, and tumor mutational burden (TMB) on treatment response to first-line atezolizumab (A) + vemurafenib (V) and cobimetinib (C) in BRAFV600 mutation–positive advanced melanoma.
Authors: Robert Caroline , Lewis Karl D. , Ascierto Paolo Antonio , Munhoz Rodrigo Ramella , Liszkay Gabriella , de la Cruz-Merino Luis , Olah Judit , Queirolo Paola , Mackiewicz Jacek , Caro Ivor , Shah Kalpit , Forbes Harper , Li Haocheng , Hertig Christian , Yan Yibing , Mckenna Edward Francis , Gutzmer Ralf , McArthur Grant A.
Published: June 2021

9523

Background: The phase 3 IMspire150 study showed that first-line A+V+C improved investigator-assessed PFS vs placebo (P)+V+C in BRAFV600E/K mutation–positive advanced melanoma (hazard ratio 0.78; P=.0249). Prior biomarker analyses showed that IFN-g or TMB > 10 mut/Mb were associated with greater PFS benefits with A+V+C (Lewis et al. J ImmunoTher Cancer 2020;8:A188-A189). We further evaluated the association of these biomarkers with outcomes. Methods: Exploratory recursive partitioning analysis (RPA) was used to model associations between PFS and age ( < 65 vs ≥65 y), Eastern Cooperative Oncology Group performance status (0 vs 1), liver metastases (yes vs no), metastatic sites (≤3 vs > 3), sum of longest tumor diameters ( < 44 mm vs ≥44 mm), baseline LDH (normal [n] vs elevated [e]), TMB ( < 10 vs ≥10 mut/Mb), PD-L1 (negative vs positive), and IFN-g (high [h; > Quartile 3; Q3] vs intermediate [ > Q1 and ≤Q3] vs low [≤Q1]). Time-to-event analyses were summarized using Kaplan-Meier estimates. Results: The RPA analysis included 208/256 (81.3%) patients (pts) from the A+V+C arm of IMspire150 for whom LDH, TMB, IFN-g, and PD-L1 data were available. RPA showed that LDH was associated with PFS. In pts treated with A+V+C and n-LDH, h-IFN-g signature was associated with longer PFS and higher rates of objective response (OR) and complete response (CR) vs low/intermediate (l/i) IFN-g (2-y PFS: 59% vs 38%; ORR: 77% vs 69%; CR: 38% vs 15%, respectively); TMB ≥10 mut/Mb was associated with more favorable outcomes in pts with e-LDH (Table). In contrast, neither IFN-g nor TMB discriminated PFS outcomes in n-LDH or e-LDH pt subgroups receiving P+V+C. Pts with e-LDH and TMB < 10 mut/Mb had poor PFS outcomes, with 2-y PFS rates of 9% and 3% and lower rates of OR (51% and 62%) and CR (5% and 9%) in the A+V+C and P+V+C arms, respectively. Similar trends were observed for duration of response (DOR), and for the subset of pts with BRAFV600E mutation–positive melanoma. A+V+C improved PFS vs P+V+C across all subgroups with the exception of e-LDH and TMB < 10. Conclusions: IFN-g and TMB discriminated PFS benefit in pts receiving A+V+C but not for those receiving P+V+C. Durable responses were observed for pts treated with A+V+C in the n-LDH + h-IFNg subgroups.[Table: see text]
Clinical characteristics of SF3B1 mutant (mut) uveal melanoma (UM) and response to immune checkpoint inhibition (ICI).
Authors: Grimes Joe , Shoushtari Alexander Noor , Orloff Marlana , Khan Shaheer , Chiuzan Cody , Hsiao Susan Jean , McDonnell Diana , Marr Brian P. , Carvajal Richard D.
Published: June 2021

9535

Background: Metastatic UM is associated with a median overall survival (OS) < 1 year (yr) and overall response rate (RR) to ICI < 18%. SF3B1 mut UM represent a clinically unique subset of UM, distinct from BAP1 mut disease, characterized by aberrant spliceosome machinery which may result in increased neoantigen presentation, increased immunogenicity, and sensitivity to ICI. To assess these hypotheses, we performed a multicenter retrospective analysis to assess the natural history and response to ICI in patients (pts) with SF3B1 mut UM. Methods: Patients were identified from institutional databases and the AACR Project GENIE Consortium. Data collected included: baseline and recurrent disease characteristics, molecular characteristics, treatments received, treatment response, and vital status. Efficacy endpoints included investigator assessed RECIST RR and OS. Results: 58 pts with deleterious SF3B1 mutations were identified: 56 R625; 1 D781G; 1 G742D. Median age at diagnosis (dx) was 52 (range, 14-87). 50% were female. 49 pts developed distant metastases. The median time from initial dx to metastasis was 6.1 years (yrs; range, 0.9 to 26.7). Initial metastatic sites (n = 48) were: liver-only (52%); non-liver-only (29%); mixed liver and non-liver disease (19%). The most common initial metastatic sites were: liver (71%), lung (29%), soft tissue (13%), lymph node (8%), and bone (4%). The median OS for all pts from time of metastasis was 3.9 years (95% confidence interval (CI), 2.3-6.2) with OS for pts with non-liver only disease at 6.2 yrs vs those with liver-only or mixed disease at 3.4 yrs (hazard ratio = 2.12, p = 0.14). 1-year OS rate from time of metastasis was 94% (95% CI, 0.86-0.99). 34 pts received ICI for metastatic disease at which time 27% had received a prior systemic therapy (median, 0; range, 0-3) and 35% had received a prior hepatic regional therapy (median, 0; range, 0-6). 15 pts received single-agent anti-PD1; 4 received ipilimumab alone; 15 received dual ICI. 10 pts received ICI with concurrent hepatic regional tx. Best response among 33 evaluable pts were: 9% partial response; 39% stable disease; 52% progressive disease. Median OS from ICI initiation was 20.2 months (95% CI, 13.1-27.4). 1-year OS from ICI initiation was 74% (95% CI, 0.59-0.90). Conclusions: SF3B1 mut UM is characterized by later development of metastases, more common involvement of extrahepatic sites, and longer OS when compared with historical datasets of molecularly unselected UM. Although a modest RR to ICI was observed, the median OS and 1-year survival rate post-ICI are numerically superior to historical controls. Given the more indolent course of SF3B1 mut UM, stratification by SF3B1 status should be included in future clinical trials.
The risk and tropism of central nervous system metastases (CNS) in patients with stage II cutaneous melanoma.
Authors: Johannet Paul , Kim Min Jae , Call Melissa , Gulati Nicholas , Zhong Judy , Mehnert Janice M. , Osman Iman
Published: June 2021

9551

Background: Recent data suggest that patients with stage III melanoma are at high enough risk for developing CNS metastases to consider routine surveillance neuroimaging (Journal of Clinical Oncology; PMID: 31990608). Given that a subset of stage II patients have a worse prognosis than stage III patients, we investigated the risk of developing brain metastases in stage II disease and compared it to the risk in stage III disease. Methods: We studied a cohort of prospectively enrolled melanoma patients who had protocol driven follow-up at New York University (NYU) Langone Health. We investigated both the incidence and time to development of CNS metastases, and explored whether the frequency of CNS metastases as a first isolated site of distant disease varies among the different stages. Results: The study cohort included a total of 1,102 patients (stage II: n = 619 with median follow-up 56.5 months; stage III: n = 483 with median follow-up 40.9 months). 85/619 (14%) stage II and 91/483 (19%) stage III patients developed CNS metastases (p = 0.03). The estimated 5-year cumulative incidence was 9% in stage IIA, 14% in stage IIB, and 29% in stage IIC patients (p = 0.0001). It was 10% in stage IIIA, 32% in stage IIIB, 23% in stage IIIC, and 49% in stage IIID (p = 0.0001). The CNS was the site of first metastasis for 32/154 (21%) stage II patients who developed distant disease compared to 28/214 (13%) stage III patients (p = 0.06). Conclusions: A subset of stage II patients are at an elevated risk for developing CNS metastases within 5 years of their initial diagnosis, which is comparable to that seen in stage III patients. The frequency of the CNS as a first site of metastasis in stage II melanoma suggests a propensity for brain tropism that cannot only be explained by a generalized pro-metastatic phenotype. Surveillance strategies that incorporate serial neuroimaging should be considered for these individuals.
Pyrexia-related outcomes upon application of an adapted pyrexia management algorithm in patients (pts) with BRAF V600: Mutant unresectable or metastatic melanoma treated with dabrafenib plus trametinib (DabTram) in the COMBI-i trial.
Authors: Ascierto Paolo Antonio , Robert Caroline , Nathan Paul D. , Dummer Reinhard , Tawbi Hussein Abdul-Hassan , Flaherty Keith T. , Ribas Antoni , Schadendorf Dirk , Green Steven , Sandalic Lali , Lau Mike R. , Romero Tonatiuh , Long Georgina V.
Published: June 2021

9560

Background: First-line DabTram has shown long-term efficacy in pts with BRAF V600–mutant unresectable or metastatic melanoma in the Phase III COMBI-d and COMBI-v trials. Data from the Phase III COMBI-i trial comparing spartalizumab plus DabTram vs placebo plus DabTram (pbo-DabTram) demonstrated efficacy in the pbo-DabTram arm, consistent with historical data. Pyrexia (single preferred term [PT]) is the most common adverse event (AE) reported with DabTram (pooled COMBI-d [data cutoff: Jan 12, 2015] and COMBI-v [data cutoff: Apr 17, 2014]: any grade, 54.2%; grade ≥ 3, 5.4%; serious pyrexia AEs leading to hospitalization, 11.8%). A new pyrexia management algorithm was implemented in the COMBI-i trial to improve pyrexia-related outcomes. We report pyrexia-related outcomes in pts treated with pbo-DabTram in the control arm of COMBI-i part 3. Methods: COMBI-i (NCT02967692) part 3 is a double-blind, Phase III trial in which pts with previously untreated BRAF V600–mutant unresectable or metastatic melanoma were randomized 1:1 to receive spartalizumab (400 mg intravenously every 4 weeks) plus Dab (150 mg orally twice daily) and Tram (2 mg orally once daily) vs pbo-DabTram. In the adapted pyrexia management algorithm, both Dab and Tram are interrupted promptly at the first symptom of pyrexia or its associated prodrome (ie, chills, rigors, night sweats, or influenza-like symptoms). Treatment at the same dose level is restarted upon the improvement of symptoms if pts are symptom free for ≥ 24 hours. Pyrexia incidence rates presented are for the single PT of pyrexia. Results: At data cutoff (July 1, 2020), median follow-up was 27.2 mo for all pts enrolled in COMBI-i part 3 (N = 532). In the DabTram control arm, 52.7% (139/264) and 3.0% (8/264) of pts had any-grade and grade ≥ 3 pyrexia, respectively. Serious pyrexia AEs were reported in 6.1% (16/264), which led to hospitalization in 5.3% (14/264). Pyrexia led to dose interruption of both Dab and Tram in 39.0% (103/264), with 1.5% (4/264) permanently discontinuing both agents. Median relative dose intensity was 97.8% for Dab and 97.7% for Tram. Conclusions: Pyrexia-related outcomes, including grade ≥ 3 pyrexia (3.0% vs 5.4%) and serious pyrexia AEs leading to hospitalization (5.3% vs 11.8%), were improved in pts treated with DabTram in COMBI-i part 3 compared with historical data from COMBI-d/v. The adapted algorithm offers a simplified approach for managing pyrexia, thereby reducing the incidence of severe pyrexia while maintaining consistent efficacy with DabTram. Clinical trial information: NCT02967692.