bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of tumor DNA in bronchial lavage as a diagnostic tool in lung cancer.
Authors: Witting Christensen Wen Sara Witting Christensen , Thomsen Caroline Brenner , Hansen Torben , Andersen Rikke Fredslund , Nederby Line , Hager Henrik , Rasmussen Kristian , Jakobsen Anders Kristian Moeller , Hilberg Ole
Published: May 2020

9020

Background: Diagnosing lung cancer requires invasive procedures with risk of complications for the patient. The HOXA9 gene is highly methylated in lung cancer, and methylated tumor DNA (meth-tDNA) in bronchial lavage has previously shown potential as a diagnostic biomarker. The aim of the present study was to validate these preliminary results. Methods: Patients were referred by the general practitioner on suspicion of lung cancer. The Danish diagnostic package includes chest and abdominal CT scan, bronchoscopy, blood tests, and histopathological or cytological verification. Twelve ml lavage fluid was collected at bronchoscopy for analysis of meth-tDNA based on droplet digital PCR according to our published method. A positive test was defined as ≥ 4 droplets containing meth-tDNA and a ratio between HOXA9 and Albumin of > 0.15%. The analysis was performed blinded to clinical data and meth-tDNA status was compared with the final diagnosis. Results: The study population was 204 consecutively enrolled patients. The material consisted of a discovery cohort (n = 105, presented at ASCO 2019) used for establishing the cut-points, and a validation cohort (n = 99). Six were excluded from analysis due to malignancy other than lung cancer and one due to failed analysis. In the discovery cohort, the sensitivity was 68.7% (95% CI 56.2-79.4%), specificity 88.2% (95% CI 72.6-96.7%), and positive predictive value (PPV) 92.0% (95% CI 80.8-97.8%). In the validation cohort, the same values were 76.9% (95% CI 63.2-87.5%), 77.3% (95% CI 62.2-88.5%), and 80.0% (95% CI 66.3-90.0%), respectively. Analyzing the entire patient material (n = 197) the sensitivity, specificity, and PPV were 72.3% (95% CI 63.3-80.1%), 82.1% (95% CI 71.7-89.8%), and 86.0% (95% CI 77.6-92.1%), respectively. The false positive samples were equally distributed among patients with cryptogenic organizing pneumonia, granulomatous inflammation, and acute inflammatory disease. The false negative samples were mainly from patients with peripheral tumor, no radiologically detectable tumor, and mesothelioma. Conclusions: Meth-tDNA in bronchial lavage holds potential as a supplementary tool in the diagnosis of lung cancer with a clinically relevant sensitivity and specificity. Routine clinical application awaits further validation in a clinical trial. [Table: see text]
Circulating tumor DNA (ctDNA) analysis predicts recurrence following surgery in patients with stage I-IIIA non-small-cell lung cancer (NSCLC): Results of GASTO1035 and GASTO1018.
Authors: Wang Si-Yu , Li Ning , Ou Wei , Cheng Chao , Kuang Peng-Peng , Wu Hui-Qi
Published: May 2020

9023

Background: Circulating tumor DNA can be detected in the plasma and serum of patients with solid tumors and has emerged as a noninvasive biomarker for dynamically monitoring tumor. Postsurgical ctDNA analysis of early-stage NSCLC may identify patients at high risk of recurrence and facilitate early intervention and personalized cancer therapy. Methods: These studies recruited 123 patients with newly diagnosed resectable stage I-IIIA NSCLC. Preoperative and postoperative plasma and postoperative tissue samples were subjected to next-generation sequencing (Nanjing Shihe Jiyin Biotechnology Inc.) using a 425 cancer-related genes panel. Peripheral blood samples were collected before surgery, postoperatively within 1 month, and every 3-6 months for up to 3 years. Plasma samples with at least 1 variants detected in tissue samples were defined as ctDNA positive. Results: After 4 exclusions, 119 eligible patients were enrolled from June 2016 to February 2019. Presurgical ctDNA was detectable in 31 of 117 (26.5%) patients and was associated with inferior recurrence-free survival (HR, 3.90, 95% CI, 1.44-10.58, P = 0.004). Similarly, ctDNA was detected in 13 of 116 (11.2%) of the first postsurgical samples and was associated with shorter RFS (HR, 3.54, 95% CI, 1.22-10.23, P = 0.002). During surveillance after surgery, ctDNA-positive patients (38/119, 31.9%) were more than 9 times more likely to experience disease recurrence than ctDNA-negative patients (HR, 9.17, 95% CI, 2.60-32.42, P <0.001). Serial ctDNA detection preceded radiologic disease recurrence by a median lead time of 4.23 months (95% CI, 0.91-7.54 months). We also observed a positive correlation between the ctDNA detection rate and the disease stage. Conclusions: These results suggest that detection of ctDNA before and after surgery is associated with the identification of a high risk of disease recurrence of resectable NSCLC. Perioperative ctDNA analyses identify disease recurrence earlier than standard-of-care radiologic imaging, and thus could facilitate personalized cancer treatment at early time points. Clinical trial information: NCT03465241 and NCT03172156.
Validation of 4-marker protein panel for the early detection of lung cancer using PLCO samples.
Authors: Fahrmann Johannes , Irajizad Ehsan , Vykoukal Jody , Patel Nikul , Dennison Jennifer B , Murage Eunice , Ostrin Edwin Justin , Hanash Samir
Published: May 2020

9024

Background: We have previously demonstrated that a protein panel consisting of ProSFTPB, CEA, CA125 and CYFRA21.1 may improve lung cancer risk assessment and has potential to define eligibility for computed tomography screening. Herein, we aimed to validate the classifier performance of the 4-marker protein panel using pre-diagnostic serum samples from the PLCO cohort. We additionally explored the additive value of diacetylspermine (DAS) with the 4-marker protein panel for identifying lung cancer cases. Methods: ProSFTPB, CEA, CA125 and CYFRA21.1 levels were measured in baseline sera of 537 lung cancer cases (76 SCLC/461 NSCLC) diagnosed within 6 years of baseline blood draw and 3772 cancer-free controls using bead-based immunoassays. DAS was measured using ultrahigh performance liquid chromatography mass spectrometry. Samples were analyzed in a double-blinded randomized fashion. Results: Overall classification performance (receiver operating characteristic area under the curve (ROAUC)) of the 4-marker panel for delineating lung cases diagnosed within 1 year and 1 to 2 years of baseline blood draw from cancer-free controls was 0.78 (95% CI: 0.74-0.82) and 0.73 (95% CI: 0.68-0.78), respectively. Classification performances of the 4-marker panel amongst lung cancer cases diagnosed within 1 year of baseline blood draw stratified into adenocarcinoma, squamous cell carcinoma and small cell lung cancer subtypes yielded ROAUCS of 0.78 (95% CI: 0.72-0.85), 0.76 (95% CI: 0.69-0.83) and 0.79 (95% CI: 0.68-0.90), respectively. Sub-analyses adjusting for smoking status yielded comparable ROAUC point estimates. Comparison of the 4-marker performance amongst non-NLST and NLST eligible lung cancer patients diagnosed within 1 year of baseline blood draw in comparison to matched cancer-free controls resulted in ROAUCs of 0.71 (95% CI: 0.63-0.79) and 0.74 (95% CI: 0.69-0.80), respectively. Analyses evaluating the additive classifier performance of serum DAS with that of the 4-marker protein panel revealed statistically significant improvement (McNemar Exact Test 2-sided p < 0.05) in sensitivity at high specificity derived from youden index for SCLC and squamous cell carcinoma cases diagnosed within 2 years from baseline blood draw, respectively, in comparison to the 4-marker protein panel alone. Conclusions: We have validated the performance of the 4-marker panel for early detection of lung cancer in the PLCO pre-diagnostic cohort. We further demonstrate that DAS can complement the 4-marker protein panel and identify more SCLC and squamous cell carcinoma cases.
The association between immune-related adverse events and efficacy outcomes with consolidation pembrolizumab after chemoradiation in patients with stage III NSCLC: an analysis from HCRN LUN 14-179.
Authors: Shukla Nikhil , Althouse Sandra K. , Sadiq Ahad Ali , Jalal Shadia Ibrahim , Jabbour Salma K. , Zon Robin , Kloecker Goetz H. , Fisher William B. , Reckamp Karen L. , Kio Ebenezer A. , Langdon Robert M. , Adesunloye Bamidele , Gentzler Ryan D. , Hanna Nasser H. , Durm Greg Andrew
Published: May 2020

9032

Background: Consolidation checkpoint inhibitor therapy (CPI) for up to 1 year following chemoradiation (CRT) is a current standard of care for pts with inoperable stage III NSCLC. However, some pts are not able to complete 1 year of CPI due to immune-related adverse events (irAES). In multiple retrospective studies, pts with stage IV NSCLC treated with CPI who experience irAEs generally receive fewer cycles of CPI without a significant detrimental effect on efficacy. The association between irAEs and outcomes with consolidation CPI after CRT has never been reported. Here we report the association between irAEs and efficacy outcomes from the HCRN LUN 14-179, a single-arm phase II trial of consolidation pembrolizumab following concurrent CRT in pts with unresectable stage III NSCLC. Methods: After completion of CRT eligible pts with stage III NSCLC without PD received pembrolizumab 200 mg IV q 3 wks for up to 1 yr. Demographics, disease characteristics, and number of cycles of pembrolizumab received were reported in pts who had any grade irAEs (except pneumonitis which included grade >2 only) [Group A] and those without irAEs (except grade 1 pneumonitis) [Group B]. Chi-square test (or Fisher's Exact test) were used for comparisons for categorical variables and Wilcoxon test for continuous variables. The Kaplan-Meier method was used to analyze time to metastatic disease (TMDD), PFS, and OS. A log-rank test was used to compare groups. Results: 92 eligible pts for efficacy analysis were enrolled from March 2015 to November 2016. 4 yr OS estimate for all pts is 46.2%. Any grade irAEs (except grade I pneumonitis) (n = 37 pts) included pneumonitis (18.5%), colitis (3.3%), increased creatinine (5.4%), elevated transaminases (3.3%), hyperthyroidism (7.6%), hypothyroidism (13.0%). Grade ≥ 2 irAEs (n = 32 pts) included pneumonitis (18.5%), hypothyroidism (10.8%), and colitis (3.3%). Group A/B: male (21/38), female (16/17), current or former smoker (35/52), stage IIIA (20/35), stage IIIB (17/20), non-squamous (21/30), squamous (16/25). Median number of pembrolizumab cycles received in Group A/B pts were 9 vs 15 (p = 0.0942) respectively. 4 yr efficacy endpoints in Groups A/B were TMDD 35.3% vs 41.3% (p = 0.83), PFS 27.8% vs 28.7% (p = 0.97), OS 43.5% vs 47.9% (p = 0.99), respectively. Conclusions: Despite receiving fewer cycles of consolidation pembrolizumab, pts who experienced any grade irAEs (excluding grade 1 pneumonitis) did not have significantly reduced efficacy outcomes. Clinical trial information: NCT02343952.
I-SABR phase II randomized study of nivolumab immunotherapy and stereotactic ablative radiotherapy in early stage NSCLC: Interim analysis adverse effects.
Authors: Chang Joe Y. , Lin Steven H. , Yao Luyang , Gandhi Saumil , Liao Zhongxing X. , Chun Stephen G. , Jeter Melenda , Welsh James William , Lee Percy , Antonoff Mara , Feng Lei , Lee J. Jack , Heymach John
Published: May 2020

9035

Background: Stereotactic Ablative Radiotherapy (SABR) provides > 95% local control and has become standard care of medically inoperable stage I NSCLC. However, cumulatively about 40% of patients develop recurrence in the regional lymph nodes, distant organs, or secondary lung cancer. Combined immunotherapy and SABR (I-SABR) may reduce these recurrences by stimulating stronger cancer specific immune response. Methods: This is an ongoing phase II randomized study (SABR vs. I-SABR) to evaluate the efficacy and toxicity of I-SABR in medically inoperable, early stage (T1-T3: < 7 cm, including multi-primary tumors), isolated recurrence NSCLC without lymph node or distant metastasis. The primary objective is event-free survival (any recurrence and/or death). Secondary objectives include rates of ≥Grade 2 toxicity. 4-D CT image guided SABR (50 Gy in 4 fractions or 70 Gy in 10 fractions) was delivered to all patients. Patients randomized to I-SABR received additional concurrent Nivolumab (240 mg, every two weeks for total of 7 doses or 480 mg every four weeks for total of 4 doses). 140 patients are anticipated to enroll. We report here interim analysis of toxicity. Results: 92 patients (median age: 72, range: 57 to 90) were enrolled and randomized (47 to SABR; 45 to I-SABR). With median follow up of 14.5 months (range 2 to 28 months), there were no treatment-related grade 4/5 adverse events. For the I-SABR arm, there was one case of possible related grade 3 dyspnea, skin rash and 2 cases of probable grade 3 fatigue. There were possible/probable treatment related 2 cases of grade 2 pneumonitis, fatigue, pruritus and 1 case of grade 2 hyperthyroidism and arthralgia. No patients discontinued treatment due to adverse effects. For the SABR arm, there were possible treatment related 1 case of grade 2 fatigue and pneumonitis. All symptoms resolved with or without treatment. Conclusions: Combined Nivolumab immunotherapy and SABR (I-SABR) appear to be well-tolerated in this fragile patient population with no grade 4/5 toxicity. All toxicities were tolerable and resolved. The major barrier for patient enrollment and/or randomization is patient’s perception of potential toxicities and additional clinic visits. Continued enrollment and additional follow up are needed to validate these findings. Clinical trial information: NCT03110978.
Artificial intelligence based on deep learning for differential diagnosis between benign and malignant pulmonary nodules: A real-world, multicenter, diagnostic study.
Authors: Xu Tao , Huang Chuoji , Liu Yaoqi , Gao Jing , Chang Huan , Yang Ronghua , Jiang Tianjiao , Cheng Zhaozhong , Yu Wencheng , Zhang Juncheng , Bai Chunxue
Published: May 2020

9037

Background: Lung cancer is the most common cancer worldwide. Artificial intelligence (AI) platform using deep learning algorithms have made a remarkable progress in improving diagnostic accuracy of lung cancer. But AI diagnostic performance in identifying benign and malignant pulmonary nodules still needs improvement. We aimed to validate a Pulmonary Nodules Artificial Intelligence Diagnostic System (PNAIDS) by analyzing computed tomography (CT) imaging data. Methods: This real-world, multicentre, diagnostic study was done in five different tier hospitals in China. The CT images of patients, who were aged over 18 years and never had previous anti-cancer treatments, were retrieved from participating hospitals. 534 eligible patients with 5-30mm diameter pulmonary nodules identified by CT were planning to confirm with histopathological diagnosis. The performance of PNAIDS was also compared with respiratory specialists and radiologists with expert or competent degrees of expertise as well as Mayo Clinic’s model by area under the curve (AUC) and evaluated differences by calculating the 95% CIs using the Z-test method. 11 selected participants were tested circulating genetically abnormal cells (CACs) before surgery with doctors suggested. Results: 611 lung CT images from 534 individuals were used to test PNAIDS. The diagnostic accuracy, valued by AUC, in identifying benign and malignant pulmonary nodules was 0.765 (95%CI [0.729 - 0.798]). The diagnostic sensitivity of PNAIDS is 0.630(0.579 – 0.679), specificity is 0.753 (0.693 – 0.807). PNAIDS achieved diagnostic accuracy similar to that of the expert respiratory specialists (AUC difference: 0.0036 [-0.0426 - 0.0497]; p = 0.8801) and superior when compared with Mayo Clinic’s model (0.120 [0.0649 - 0.176], p < 0·0001), expert radiologists (0.0620 [0.0124 - 0.112], p = 0.0142) and competent radiologists (0.0751 [0.0248 - 0.125], p = 0.0034). 11 selected participants were suggested negative in AI results but positive in respiratory specialists’ result. 8 of them were malignant in histopathological diagnosis with tested more than 3 CACs in their blood. Conclusions: PNAIDS achieved high diagnostic accuracy in differential diagnoses between benign and malignant pulmonary nodules, with diagnostic accuracy similar to that of expert respiratory specialists and was superior to that of Mayo Clinic’s model and radiologists. CACs may be able to assist CT-based AI in improving their effectiveness but it still need more data to be proved. Clinical trial information: ChiCTR1900026233.
Clinical impact of targetable gene alterations on therapeutic outcomes in stage II/III locally advanced non-small cell lung cancer patients.
Authors: Zenke Yoshitaka , Matsumoto Shingo , Kato Terufumi , Miyamoto Shingo , Imakita Takuma , Mitsudomi Tetsuya , Aono Hiromi , Ushio Ryota , Furuya Naoki , Nishino Kazumi , Takata Saori , Nakao Mika , Hara Satoshi , Tachihara Motoko , Sekine Akimasa , Sakakibara-Konishi Jun , Toyozawa Ryo , Yoh Kiyotaka , Goto Koichi
Published: May 2020

9038

Background: The clinical significance of genetic alterations in stage II/III non-small cell lung cancer (NSCLC) patients has not yet been clarified. We have prospectively analyzed NSCLC patients for cancer-related gene alterations and have followed up clinical course of the patients, establishing a large-scale clinico-genomic database in our nationwide genome screening project (LC-SCRUM-Japan). Methods: Submitted tumor samples were subjected to a targeted next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay. Therapeutic and prognostic data were collected and updated every year. Results: Since March 2015 to May 2019, 5166 non-squamous NSCLC patients from 263 institutions had been enrolled in the LC-SCRUM-Japan, and 754 of them were diagnosed as stage II/III. The median age of the 754 patients was 67 years (range, 21-92), and 503 (67%) were male, 595 (79%) smokers and 631 (84%) stage III. Of 640 available samples, 258 (40%) had targetable gene alterations, comprising 106 KRAS mut, 42 EGFR mut, 29 BRAF mut, 20 MET ex14skip/amp, 16 ALK fus, 12 ROS1 fus, 11 ERBB2 ex20ins, 8 RET fus, 7 EGFR ex20ins, 5 AKT1 mut, 1 NRG1 fus, 1 FGFR2/3 fus. In patients who received surgery (n = 159), 3-year disease-free survival rate was worse in patients with targetable gene alterations than in those without (40% vs 58% months; p = 0.03). In patients who received cytotoxic chemo-radiotherapy (n = 148), the response rate was similar in patients with targetable gene alterations and those without (70% vs. 77%); however, 3-year progression-free survival rate tended to be shorter in patients with targetable gene alterations than in those without (19% vs 35%; p = 0.08). Conclusions: In stage II/III NSCLC, the total frequency of targetable gene alterations was similar to that previously evaluated in our stage IV cohort (45%), and the current standard therapies showed early progression in the targetable gene-altered patients. A novel effective multimodality treatment in combination with targeted therapies is needed for this population.
Real-world survey of pneumonitis/radiation pneumonitis among patients with locally advanced non-small cell lung cancer treated with chemoradiotherapy after durvalumab approval: A multicenter retrospective cohort study (HOPE-005/CRIMSON).
Authors: Saito Go , Oya Yuko , Taniguchi Yoshihiko , Kawachi Hayato , Fujimoto Daichi , Matsumoto Hirotaka , Iwasawa Shunichiro , Suzuki Hidekazu , Niitsu Takayuki , Miyauchi Eisaku , Yokoi Takashi , Mitsui Miho , Uenami Takeshi , Sakata Yoshihiko , Arai Daisuke , Okada Asuka , Hara Satoshi , Teraoka Shunsuke , Kokubo Masaki
Published: May 2020

9039

Background: Durvalumab was approved as a consolidation therapy after chemoradiotherapy (CRT) for locally advanced non-small cell lung cancer (NSCLC) and established as the standard of care. However, since the approval of durvalumab, little has been reported on the frequency, severity, or clinical course of pneumonitis/radiation pneumonitis throughout the course of CRT. Methods: We conducted a 17-center, retrospective cohort study of consecutive patients with locally advanced NSCLC who received concurrent chemoradiotherapy (CCRT) with platinum-based chemotherapy between May 2018 and May 2019. Results: A total of 275 patients were included; their median age was 69.9 (range, 40.3-87.5), mean V20 was 19.4% (range, 1.4-37.9), and mean "mean lung dose" was 10.9 Gy (range, 1.5-31.3). Of these, 204 patients received durvalumab consolidation therapy (74.2%). Median follow-up time from the initiation of CCRT was 8.4 months (range, 1.5-15.7). During follow-up, 225 patients (81.8%) developed any-grade pneumonitis/radiation pneumonitis. Of these, more than half (134 of 225) were asymptomatic (grade 1), 18 (6.5%) were ≥grade 3, and 4 patients (1.5%) had fatal pneumonitis/radiation pneumonitis. By the time of initial assessment of response to CCRT, 64 (23.3%) patients had developed radiation pneumonitis. Logistic regression revealed that only V20 ≥25 % was an independent risk factor of symptomatic (≥grade 2) pneumonitis/radiation pneumonitis (OR: 2.74, 95% CI: 1.35-5.53, p = 0.0045). Of the 275 patients, 67 were treated with corticosteroids for pneumonitis/radiation pneumonitis (24.7%), and 14 (5.1%) needed home oxygen therapy after the treatment of pneumonitis/radiation pneumonitis. Among patients treated with corticosteroids, 21 patients received durvalumab rechallenge. Of the 21 patients, 6 (29%) showed pneumonitis/radiation pneumonitis relapse, of which 3 (14%) resulted in suspension of durvalumab rechallenge, but none were fatal. Conclusions: Although over four-fifths of the patients treated with CCRT after the approval of durvalumab developed pneumonitis/radiation pneumonitis, more than half of them were asymptomatic, and ≥grade 3 events accounted for 6.5%. Sometimes patients needed corticosteroid therapy, which was in many occasions effective, and some also underwent durvalumab rechallenge. V20 was an independent risk factor of symptomatic pneumonitis/radiation pneumonitis.
Neoadjuvant nivolumab (N) plus cisplatin (C)/pemetrexed (P) or cisplatin /gemcitabine (G) in resectable NSCLC.
Authors: Zinner Ralph , Axelrod Rita , Solomides Charalambos C , Cowan Scott , Leiby Benjamin , Bhatia Avnish K , Sundermeyer Mark L. , Hooper D. Craig , Harshyne Larry , Lu-Yao Grace L. , Quereda-Bernabeu Belen C , Whang Sung C , OHara Suzanne C , Vernau Daniel C , Werner-Wasik Maria , Lu Bo , Johnson Jennifer M , Scott Walter C , Argiris Athanassios , Evans Nathaniel R.
Published: May 2020

9051

Background: Patients (pts) with resectable stage IB (≥4cm)-IIIA non-small-cell lung cancer (NSCLC) derive modest overall survival benefit with neoadjuvant or postoperative adjuvant chemotherapy. Neoadjuvant therapy can speed the discovery of promising regimens by using pathologic response as a surrogate for OS. Major pathologic response (MPR), defined as < 10% viable tumor, was strongly associated with improved OS. PD-(L)1 checkpoint inhibitors in combination with chemotherapy are standard of care in advanced NSCLC. We hypothesize that the addition of N to neoadjuvant CP or CG will increase the MPR rate compared to historical controls. Methods: This is an investigator-initiated trial for pts with newly diagnosed AJCC 8th stage IB (≥4cm)-IIIA squamous or non-squamous EGFR/ALK WT NSCLC with a plan to have surgery. Pts receive 3 courses of N 360mg IV q 3w added to C 75mg/m2 IV q 3w plus P 500 mg/m2 IV q 3wks or G 1250mg/m2 IV d1, d8 with surgery 3 wks after the last dose. The primary objective is MPR. To estimate pathologic response, the resected pathology specimens are cut >1 section/cm. Using the Aperio Digital scanning system©, slides were imaged, and then annotated by at least 2 pathologists for viable tumor vs. treatment effect with respective areas then automatically calculated and percentage of viable tumor calculated. Our primary endpoint will be reached if 10/34 (29%) planned pts have at least an MPR. Results: From 6/2018-8/2019, 13 pts were enrolled all of whom had surgery. Median age was 69 (49-80), 38% women, 31% nonsquamous, 54% stage IIIA, and 77% PD-L1 positive (≥1%, SP263). Pre-surgical grade 3 toxicity occurred in 2/13 pts, one of whom was changed to carboplatin for courses 2 and 3. Grade 3 toxicities were neutropenia (2/13), anemia (1/13), and renal (1/13). One pt. developed hypothyroidism 4 mos after surgery. One pt died 6 weeks after surgery from complications unrelated to study drugs. Our primary endpoint was met; 11/13 (85%), had at least an MPR with 6/13 (46%) and 5/13 (38%) having an MPR and pCR respectively. Radiologic response rate was 46% (PR 5, CR 1). Pts with either PD-L1+ or PD-L1- had MPRs. With a median follow-up of 10 months there are no recurrences. Conclusions: The combination of nivolumab added to platinum doublets was well tolerated. The primary endpoint of MPR in at least 10/34 pts was surpassed with MPR or pCR in 11/13 pts post-surgery. MPR was seen independent of PD-L1 score. Exploratory outcomes assessing markers of immune bias in tumor tissue and plasma are in process. Clinical trial information: NCT03366766.
MiST1: A phase IIa trial of rucaparib in patients harbouring BAP1/BRCA1 deficient relapsed malignant mesothelioma.
Authors: Fennell Dean Anthony , Darlison Liz , Wells-Jordan Peter , Richards Catherine Jane , Gaba Aarti , Poile Charlotte , Cowley Caroline , Dawson Alan G , Scotland Molly , Bhundia Vina , Morgan Bruno , Anthony Sarah , Nicholson Adrian , Brookes Cassandra , Mohammed Seid , Branson Amy , King Amy , Thomas Anne L.
Published: May 2020

9057

Background: Malignant Mesothelioma (MM) remains an incurable cancer lacking effective treatments in the relapsed setting. Personalised therapy is still in its infancy. Homologous recombination (HR) deficiency associated with BRCA1 mutation has been shown to predict sensitivity to inhibition of poly-ADP ribose. In MM, BRCA1 associated protein 1 carboxy-terminal hydrolase (BAP1) is frequently mutated. It regulates both HR, and BRCA1 expression which is lost in 38% of mesotheliomas. Mesothelioma Stratified Therapy 1 (MiST1) was designed to test the hypothesis that BAP1/BRCA1 negative mesotheliomas would exhibit defective HR and exhibit sensitivity to PARP inhibition. Methods: MiST1 was a single centre, open label single arm phase IIa design with prospective molecular stratification; cytoplasmic/negative BAP1 or BRCA1 deficient MM was deemed eligible. Treatment was 600mg BD rucaparib (R) PO daily every 28 days for 6 cycles or until disease progression, unacceptable toxicity, withdrawal or death. Primary outcome was disease control rate at 12 weeks (DCR12w); secondary outcomes safety and toxicity profile, objective response rate (ORR) and DCR at 24 weeks (DCR24w). The null hypothesis states the true DCR12w is less than or equal to 25% and was tested against a one-sided alternative hypothesis that the DCR12w will be equal to or greater than 50%. Results: Between February 2019 and June 2019, 26 patients (pts) were eligible and consented to MiST1, median age 65.5 years, 85% are male and 15% female. Of these pts 15% had an ECOG performance status (PS) of 0 and 85% had an ECOG PS of 1. Molecular eligibility was 89% for BAP1 alone, 50% BRCA1 alone, and 39% BAP1+BRCA1. Primary tumour site was thoracic (96%) and subtype epithelioid (81%). DCR12w was 57.7% (95% CI, 36.9 - 76.7), DCR24w was 23.1% (95% CI, 9.0 – 43.7) and ORR was 11.5% (95%CI, 2.5 – 30.2). R was well tolerated with 9% (15/166) grade (G) 3/4 toxicities seen in 10 pts (38%), with no G5 toxicities. The most common adverse events were nausea occurring in 18 pts (69%), fatigue in 14 pts (54%), and decreased appetite in 10 pts (38%). Six cycles of R was received by 8 pts (30.8%). Dose reductions occurred in 9 pts (n = 8; 1 dose and n = 1; 2 doses). Dose delays occurred in 14 pts. Conclusions: MiST1 using the PARP inhibitor R met its primary endpoint of disease control rate at 12 weeks, showing promising efficacy with manageable toxicity. HR deficiency mutation signature enrichment is being investigated to refine the identification of responders to PARP inhibition. PARP inhibition warrants further investigation in MM. Clinical trial information: NCT03654833.
Correlation of decreased expression of PD-L1 on circulating tumor cells and clinical benefit in SCLC Patients treated with RRx-001, a CD47 downregulator, in a phase II trial.
Authors: Carter Corey , Tomita Yusuke , Yuno Akira , Baker Jonathan , Lee Min-Jung , Lee Sunmin , Caroen Scott , Quinn Mary Flanagan , Oronsky Bryan , Reid Tony R. , Cabrales Pedro , Abrouk Nacer , Trepel Jane B
Published: May 2020

9062

Background: In a Phase 2 trial called QUADRUPLE THREAT (QT) (NCT02489903), where 2nd line+ small cell lung cancer (SCLC) patients were treated with RRx-001 and a platinum doublet, the programmed death-ligand 1 (PD-L1) status of circulating tumor cells (CTCs) in 14 patient samples was evaluated. Methods: 26 consented patients received weekly RRx-001 4 mg followed by a reintroduced platinum doublet; epithelial cell adhesion molecule (EPCAM+) CTCs from 10 ml of blood on two consecutive timepoints cycle 1 day 1 and cycle 3 day 8 (cycle duration = 1 week) were detected by EpCAM-based immunomagnetic capture and flow cytometric analysis. CTCs were further characterized for protein expression of PD-L1. Tumor response was classified as partial or complete response based on the response evaluation criteria in solid tumors (RECISTv1.1) measured every 6 weeks. Results: The analyzed clinical data set comprised 14 RECIST-evaluable patients. 50% were females (7/14) and the median age (years) at baseline was 64.5 (Min = 48.5, Max = 84.2, SD = 10.3). The logistic model McFadden goodness of fit score (0 to 100) is 0.477, which is a strong correlation value. The logistic model analyzing the association of CTC PD-L1 expression at two timepoints and response had an approximate 92.8% accuracy in its prediction of clinical benefit (SD/PR/CR). Accuracy is defined in the standard way as 1- (False positive rate + False negative rate). The estimated ROC displayed in Figure 1 suggests a ROC AUC of 0.93 (95% CI: 0.78, 0.99), an excellent measure of performance. Conclusions: Reduction of PD-L1 expression was correlated with good clinical outcome after RRx-001 + platinum doublet treatment. PD-L1 expression reduction in favor of RRx-001 RECIST clinical benefit was clinically significant as compared to non-responders with progressive disease (PD). In the ongoing SCLC Phase 3 study called REPLATINUM (NCT03699956), analyses are planned to correlate response and survival with expression of CD47 and PD-L1 on CTCs. Clinical trial information: NCT02489903.
Early ctDNA response assessment for prediction of platinum sensitivity in small cell lung cancer.
Authors: Murciano-Goroff Yonina R. , Hui Angela B. , Chabon Jacob J. , Moding Everett J , Lebow Emily S. , Araujo-Filho Jose A. , Isbell James M. , Jones David Randolph , Ginsberg Michelle S. , Myers Mackenzie L. , Offin Michael , Drilon Alexander E. , Hellmann Matthew David , Lai Wei-Chu Victoria , Reis-Filho Jorge S. , Razavi Pedram , Rudin Charles M. , Alizadeh Ash A. , Li Bob T. , Diehn Maximilian
Published: May 2020

9067

Background: Small cell lung cancer (SCLC) is an aggressive disease, characterized by inevitable chemotherapy resistance and rapid progression. We hypothesized that circulating tumor DNA (ctDNA) analysis can rapidly identify sensitivity to platinum-based therapy. Methods: Patients with SCLC at Memorial Sloan Kettering Cancer Center underwent serial plasma collections, including prior to the start of treatment and prior to Cycle 2 Day 1 of therapy (C2D1). Tumor mutations were identified from pre-treatment biopsies by MSK-IMPACT and/or pre-treatment plasma by CAncer Personalized Profiling by deep Sequencing (CAPP-Seq). Median variant allele fraction (VAF) of all mutations was monitored on subsequent blood draws using CAPP-Seq. Progression free survival (PFS) was measured from the time of first pre-treatment blood draw. Results: Plasma was collected from 19 patients treated with carboplatin and etoposide, including three who received concurrent atezolizumab. Seven were female, and mean age was 64.5 years. ctDNA was detected in 17 patients (89%), including in the two patients in our series with limited stage disease. The most common mutations were in TP53 and RB1 in 14 and 6 patients, respectively. Fourteen patients had available plasma at C2D1. At baseline prior to treatment, median VAF did not differ significantly between radiologic responders and non-responders (9.4% versus 30.3%, p = 0.35). After one cycle of chemotherapy, the VAF percent decrease was significantly more in responders versus non-responders (-96.9% versus -10.3%, p < 0.001). Median VAF was therefore significantly lower by C2D1 in patients who responded compared to non-responders (0.51% versus 27.2%, p = 0.02). Those who ultimately responded to therapy all had a > 2 fold decrease in VAF by C2D1. With a median follow-up of 180 days, PFS was significantly longer in patients with > 2 fold decrease in VAF by C2D1 (6.4 versus 1.9 months, log rank p < 0.001). Conclusions: A 2-fold decrease in plasma VAF by C2D1 predicted platinum-sensitivity in SCLC and was associated with longer PFS. ctDNA may permit early assessment of benefit and expedite alternative treatment options for those without significant decrease in median VAF after one cycle of therapy.
RESILIENT part I, an open-label, safety run-in of liposomal irinotecan in adults with small cell lung cancer (SCLC) who have progressed with platinum-based first-line (1L) therapy: Subgroup analyses by platinum sensitivity.
Authors: Spigel David R. , Paz-Ares Luis G. , Chen Yuanbin , Jove Maria , Juan-Vidal Oscar , Rich Patricia , Hayes Theresa M. , Gutierrez Calderon M Vanesa , Bernabe Caro Reyes , Navarro Alejandro , Dowlati Afshin , Zhang Bin , Moore Yan , Wang Haofei Tiffany , Kokhreidze Jaba , Nazarenko Natalya , Ponce Aix Santiago , Bunn Paul
Published: May 2020

9069

Background: Most patients with extensive SCLC develop drug resistance to platinum-based 1L therapy or discontinue for other reasons, and second-line (2L) therapies are limited. RESILIENT (NCT03088813) is a two-part phase 2/3 study assessing the safety, tolerability and efficacy of 2L liposomal irinotecan monotherapy in adults with SCLC who progressed with platinum-based 1L therapy. Preliminary data from RESILIENT part 1 (cut-off May 8 2019; ≥ 12 weeks follow-up) showed that liposomal irinotecan 70 mg/m2 free base every 2 weeks was generally well tolerated and had encouraging antitumor activity (Paz-Ares et al. WCLC 2019 OA03.03). Objective response rate (ORR; secondary endpoint) was 44% (11/25). Here we report efficacy analyses in post hoc subgroups by platinum sensitivity. Methods: RESILIENT part 1 was an open-label, single-arm study comprising dose-finding and dose-expansion phases. Eligible patients were aged ≥ 18 y, with an ECOG performance status score of 0/1 and adequate organ function; a single line of prior immunotherapy was allowed. Participants received liposomal irinotecan 70 mg/m2 or 85 mg/m2 free base every 2 weeks, with tumor assessments every 6 weeks (RECIST v1.1). Analyses were undertaken for the dose-finding phase recommended dose (RD) in subgroups of platinum-resistant/sensitive patients (with/without progression within 90 days from completion of 1L therapy). Results: During dose finding, 5 patients received liposomal irinotecan 85 mg/m2 (deemed not tolerable; dose-limiting toxicity) and 12 received 70 mg/m2 (deemed tolerable; RD for dose-expansion phase in which 13 more patients were included). Analyses included all 25 patients receiving the RD (mean exposure, 13.95 weeks [median 14.86; SD 7.222]). In the platinum-sensitive subgroup (33.3% men; median age 62.0 y) ORR was 53.3% (8/15) and 12-week disease control rate (DCR12wks) was 60% (9/15); in the platinum-resistant subgroup (50% men, median age 58.0 y) both ORR and DCR12wks were 30% (3/10). Overall and progression-free survival (secondary endpoints) are not yet mature. Conclusions: ORR and DCR12wks were numerically higher in platinum-sensitive than in platinum-resistant patients with SCLC who had progressed with platinum-based 1L therapy before receiving 2L liposomal irinotecan 70 mg/m2 in this phase 2 study. RESILIENT part 2, an ongoing, phase 3, randomized controlled trial vs topotecan, will provide further data. Clinical trial information: NCT03088813.
Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA.
Authors: Reck Martin , Ciuleanu Tudor-Eliade , Dols Manuel Cobo , Schenker Michael , Zurawski Bogdan , Menezes Juliana , Richardet Eduardo , Bennouna Jaafar , Felip Enriqueta , Juan-Vidal Oscar , Alexandru Aurella , Sakai Hiroshi , Scherpereel Arnaud , Lu Shun , John Thomas , Carbone David Paul , Meadows-Shropshire Stephanie , Yan Jinchun , Paz-Ares Luis G.
Published: May 2020

9501

Background: NIVO + IPI was shown to improve overall survival (OS) and durability of response vs chemo in 1L advanced NSCLC in CheckMate 227 Part 1, regardless of PD-L1 expression. We hypothesized that a limited course of chemo combined with NIVO + IPI could provide rapid disease control while building on the durable OS benefit seen with dual PD-1 and CTLA-4 inhibition. CheckMate 9LA (NCT03215706) is a phase 3 randomized study evaluating NIVO + IPI + 2 cycles chemo vs chemo in 1L stage IV/recurrent NSCLC. Methods: Adults with tx-naive, histologically confirmed stage IV/recurrent NSCLC, ECOG performance status 0–1, and no known sensitizing EGFR/ALK alterations were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles) (n = 361) or chemo (4 cycles) alone (n = 358), stratified by PD-L1 (< 1% vs ≥ 1%), sex, and histology (squamous vs non-squamous). Chemo was based on histology. Pts with non-squamous NSCLC in the chemo-only arm could receive optional pemetrexed maintenance. Pts were treated with immunotherapy until disease progression, unacceptable toxicity, or for 2 y. The primary endpoint was OS; the interim analysis using Lan–DeMets alpha spending function with O’Brien–Fleming boundary was planned at ~80% information fraction (ie, after observing ~322 total events). Secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by blinded independent central review, and efficacy by PD-L1 subgroups. Exploratory endpoints included safety/tolerability. Results: Baseline characteristics were balanced across arms. At a preplanned interim analysis (minimum follow-up 8.1 mo), OS was significantly prolonged with NIVO + IPI + chemo vs chemo (HR 0.69, 96.71% CI: 0.55–0.87; P = 0.0006); statistically significant improvements in PFS and ORR were seen. With longer follow-up (minimum 12.7 mo), NIVO + IPI + chemo vs chemo continued to provide longer OS; median 15.6 vs 10.9 mo (HR 0.66, 95% CI: 0.55–0.80); 1-y OS rates were 63 vs 47%. Clinical benefit was consistent across all efficacy measures in key subgroups including by PD-L1 and histology. Grade 3–4 tx-related adverse events were reported in 47 vs 38% of pts in the NIVO + IPI + chemo vs chemo arms, respectively. Conclusions: CheckMate 9LA met its primary endpoint: a statistically significant improvement in OS was observed with NIVO + NSCLC-optimized IPI + a limited course of chemo vs chemo (4 cycles) in 1L advanced NSCLC. No new safety signals were reported. Clinical trial information: NCT03215706 .
Efficacy and safety of the antibody-drug conjugate (ADC) SAR408701 in patients (pts) with non-squamous non-small cell lung cancer (NSQ NSCLC) expressing carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5).
Authors: Gazzah Anas , Ricordel Charles , Cousin Sophie , Cho Byoung Chul , Calvo Emiliano , Kim Tae Min , Helissey Carole , Kim Jin-Soo , Vieito Maria , Boni Valentina , Chadjaa Mustapha , Hospitel Marie , Yoruk Semra , Barlesi Fabrice
Published: May 2020

9505

Background: We report updated safety and efficacy of DM4-conjugated anti-CEACAM5 ADC from the expansion part of the first-in-human study (NCT02187848; Gazzah A et al. J Clin Oncol. 2019;37:15, 9072) in 92 NSQ NSCLC pts. Methods: CEACAM5 expression was assessed by immunohistochemistry on archived tumor samples. Two cohorts of pts have been analyzed: moderate and high expressors, with CEACAM5 expression at ≥2+ intensity between ≥1% to < 50% and ≥50% of the tumor cell population, respectively. SAR408701 was administered at 100 mg/m2 IV every 2 weeks. Tumor assessments were done every 4 cycles (8 weeks). Primary endpoint was overall response rate (ORR). Results: As of January 2020, 92 pts were treated: 28 moderate and 64 high expressors, with median age 62.5 years (31–91; 42.4% of pts ≥65), 51.1% male, 71.7% ECOG PS ≥1; median of 3 prior treatments (1–10 lines) for advanced disease, including anti-tubulin agents (60.9%) and anti-PD1/PD-L1 (75%). In the moderate expressor cohort, 2 confirmed partial responses (PR) were observed (ORR 7.1%). In the high expressor cohort, 13 pts had confirmed PRs (ORR 20.3% [95% confidence interval 12.27%–31.71%]); 27 (42.2%) had stable disease; ORR of 17.8% was observed in 45 pts who had prior anti-PD1/PD-L1. Pts had a median of 7 (1–49) cycles; median relative dose intensity was 0.98. Six pts discontinued due to treatment-emergent adverse events (TEAEs). Most frequent TEAEs (all grades) were asthenia (38.0%), keratopathy/keratitis (38.0%), peripheral neuropathy (26.1%), dyspnea (23.9%), and diarrhea (22.8%). 31 pts had dose modification due to a TEAE, including dose reduction for keratopathy/keratitis in 10 pts. Hematological toxicity included leukopenia (14.4%), neutropenia (4.4%), and thrombocytopenia (13.3%). Grade ≥3 TEAEs occurred in 47.8% of pts and were assessed as drug-related in 15.2%. Conclusions: SAR408701 shows promising antitumor activity in heavily pretreated advanced NSQ NSCLC pts with high CEACAM5 expression. SAR408701 was well tolerated, with minimal hematological toxicity compared to conventional chemotherapy; keratopathy was reversible and manageable with dose modification. These data support the activity of SAR408701 in NSQ NSCLC CEACAM5 high expressors. A phase 3 trial evaluating the activity of CEACAM5-DM4 ADC monotherapy in comparison with docetaxel in NSQ NSCLC CEACAM5 high expressors after failure of standard first line chemotherapy and anti-PD1/PD-L1 is underway. Clinical trial information: NCT02187848 .
Registrational dataset from the phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced RET fusion+ non-small cell lung cancer (NSCLC).
Authors: Gainor Justin F. , Curigliano Giuseppe , Kim Dong-Wan , Lee Dae Ho , Besse Benjamin , Baik Christina S , Doebele Robert C , Cassier Philippe Alexandre , Lopes Gilberto , Tan Daniel Shao-Weng , Garralda Elena , Paz-Ares Luis G. , Cho Byoung Chul , Gadgeel Shirish M. , Thomas Michael , Liu Stephen V. , Clifford Corinne , Zhang Hui , Turner Christopher D. , Subbiah Vivek
Published: May 2020

9515

Background: Pralsetinib is an investigational, highly potent, selective RET kinase inhibitor targeting oncogenic RET alterations. We provide the registrational dataset for pts with RET fusion+ NSCLC with and without prior treatment from the global ARROW study. Methods: ARROW (75 sites in 11 countries; NCT03037385) consists of a phase I dose escalation to establish recommended phase II dose (400 mg once daily [QD] orally) and phase II expansion cohorts defined by tumor type and/or RET alteration. Primary objectives were overall response rate (ORR; blinded independent central review per RECIST v1.1) and safety. Efficacy analyses are shown for response-evaluable pts (REP) with RET fusion+ NSCLC who initiated 400 mg QD pralsetinib by July 11 2019 and safety for all pts (regardless of diagnosis) treated with 400 mg QD. Results: As of November 18 2019, 354 pts with advanced solid tumors had received pralsetinib at starting dose of 400 mg QD with median follow-up 8.8 months. ORR, disease control rate (DCR), and % of pts with tumor size reduction are shown in the table for pts with metastatic RET fusion+ NSCLC (n=116; 72% KIF5B; 16% CCDC6; 12% other/fusion present but type unknown) and with prior platinum treatment (n=80) or without prior systemic treatment (n=26). ORR was similar regardless of RET fusion partner, prior therapies, or central nervous system involvement. Overall there were 7 (6%) complete responses, 4 (5%) in prior platinum pts and 3 (12%) in treatment naïve pts; median time to response overall was 1.8 months and median duration of response (DOR) was not reached (95% CI, 11.3–NR). In the safety population (n=354), most treatment-related adverse events (TRAEs) were grade 1-2, and included increased aspartate aminotransferase (31%), anemia (22%), increased alanine aminotransferase (21%), constipation (21%) and hypertension (20%). 4% of pts in the safety population (all tumor types) discontinued due to TRAEs. Conclusions: Updated, registrational, centrally reviewed data demonstrate that pralsetinib has rapid, potent, and durable clinical activity in pts with advanced RET fusion+ NSCLC regardless of RET fusion genotype or prior therapies, and QD oral dosing is well-tolerated. Clinical trial information: NCT03037385 . [Table: see text]
Exon-16-skipping ERBB2 (ERBB2ΔEx16) as a novel resistance mechanism against EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC).
Authors: Zhao Xin , Jin Linling , Yu Man , Ou Qiuxiang , Bao Hua , Wu Xue , Shao Yang , Fan Min
Published: May 2020

9528

Background: In addition to ERBB2 amplification/protein overexpression, activating ERBB2 alterations have been increasingly discovered in diverse human cancers with varying incidence. ERBB2ΔEx16 is an alternatively spliced isoform of ERBB2, lacking the entire exon 16 which encodes a small extracellular domain. ERBB2ΔEx16 was recently reported to lead to oncogenic activation of ERBB2 and osimertinib resistance in EGFR T790M+ non-small cell lung cancer (NSCLC). Methods: A total of 38,680 Chinese cancer patients whose tumor specimen or circulating cell-free DNA underwent genomic profiling by targeted next-generation sequencing of cancer-related genes were retrospectively reviewed. Clinicopathological features and treatment history of ERBB2ΔEx16+ patients were evaluated. RNA sequencing was performed to validate the presence of exon-16-skipping ERBB2 at the transcriptional level. Results: A total of eighteen ERBB2ΔEx16+ patients (11 NSCLC, 2 colorectal cancer, 2 gastric cancer, and 3 others) were identified (0.047%, 18/38,680). ERBB2 exon 16 skipping may result from large fragment deletion spanning the whole or partial region of exon 16 (72.2%, 13/18), base substitution at the splice acceptor site (16.7%, 3/18) and deletion of the splice donor site (11.1%, 2/18). ERBB2 exon 16 skipping, including large fragment deletion and splice site deletion, was validated at the RNA level by RNA sequencing in 3 patients with available samples. Co-occurrence of ERBB2 amplification and ERBB2 mutations were found in 83.3% (15/18) and 50% (9/18) of cases, respectively. Concurrent copy number variations were prevalent in CDK12 (55.6%, 10/18), CDKN2B (44.4%, 8/18), NKX2.1 (38.9%, 7/18) and PTPRD (33.3%, 6/18). Among the 11 cases of ERBB2ΔEx16+ NSCLC, 9 had coexisting activating EGFR mutations (exon 19 deletions, exon 21 L858R) and received prior treatment with EGFR tyrosine kinase inhibitors (TKIs), with 2 harboring acquired EGFR T790M mutation and 1 EGFR copy number gain. Further analysis of the matched pretreatment samples in 3 EGFR-mutated NSCLC patients confirmed that ERBB2ΔEx16 was acquired during EGFR TKI therapy. In the 7 cases of other cancers, 4 to 31 non- ERBB2 mutations were identified in each sample, with TP53 being the most frequently mutated gene. Conclusions: Our data suggest that ERBB2ΔEx16 may be a general mechanism of EGFR TKI resistance in a subset of EGFR-mutated NSCLC patients, in addition to being an oncogenic driver as reported in some solid malignancies including colorectal, gastric and ovarian cancers.