bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of carfilzomib, dexamethasone, daratumumab (KdD) twice-weekly at 56 mg/m2 and once-weekly at 70 mg/m2 in relapsed or refractory multiple myeloma (RRMM): Cross-study comparison of candor and MMY1001.
Authors: Leleu Xavier , Beksac Meral , Chou Takaaki , Dimopoulos Meletios A. , Yoon Sung-Soo , Prince H. Miles , Pour Ludek , Shelekhova Tatiana , Chari Ajai , Khurana Monica , Obreja Mihaela , Qi Ming , Oriol Albert , Siegel David Samuel DiCapua
Published: May 2020

8526

Background: CANDOR, a randomized phase 3 study, showed significantly improved progression-free survival (PFS) and overall response rate (ORR) for twice-weekly KdD 56 mg/m2(TW KdD56) vs Kd in RRMM, with a 37% risk reduction in disease progression or death (Usmani, 2019). The benefit of once-weekly carfilzomib (K) at 70mg/m2 for the same triplet, KdD (OW KdD70), in RRMM was shown in the nonrandomized MMY1001 study. We performed robust cross-study comparisons to investigate how TW KdD56 compares to OW KdD70. Methods: For alignment of inclusion criteria, the primary analysis set for this cross-study comparison included individual data from CANDOR pts with prior exposure to bortezomib and immunomodulatory drug, and all pts in MMY1001. Propensity score method (Rambaldi, 2019; Kumar, 2019) allowed reliable cross-study comparison, controlling for baseline prespecified covariates such as age, creatinine clearance, performance status, prior treatment exposure/refractoriness, and time from initial diagnosis and relapse. Propensity score adjustment based on inverse probability of treatment weighting (IPTW) was implemented on efficacy endpoints, while safety was evaluated side-by-side. Results: The unadjusted and adjusted propensity score comparison of CANDOR and MMY1001 showed similar efficacy in terms of ORR and PFS in the TW KdD56 and OW KdD70 groups (Table). As propensity score comparisons were for efficacy only, safety comparisons between CANDOR and MMY1001 included differing sample sizes and treatment duration (Table). The safety of KdD56 and KdD70 was consistent with the known safety profiles of individual study treatments. Conclusions: OW KdD70 is an efficacious dosing option with favorable benefit-risk, comparable to TW KdD56. The OW KdD70 dosing option represents a more convenient regimen that might encourage adherence and potentially lead to better outcomes for RRMM pts. Clinical trial information: NCT03158688 . [Table: see text]
Correlation between 24-hour proteinuria and spot urine albumin to creatinine ratio in systemic light chain amyloidosis.
Authors: Visram Alissa , Al Saleh Abdullah S. , Muchtar Eli , McDonald Jennifer , Parmar Harsh V , Vaxman Iuliana , Dispenzieri Angela , Buadi Francis , Gertz Morie A. , Leung Nelson
Published: May 2020

8549

Background: Proteinuria evaluation is essential for diagnosing and monitoring of renal involvement in light chain (AL) amyloidosis. A 24 hour protein collection (24h UP) is the gold standard for proteinuria assessment however it is cumbersome and can be inaccurate. A spot urine albumin to creatinine ratio (uACR) has been proposed as a convenient method to estimate 24hUP. We aimed to validate the correlation between uACR and 24hUP in a large cohort of patients. Methods: We retrospectively studied systemic AL amyloidosis patients evaluated between 2010 and 2019 at Mayo Clinic, with a uACR and 24hUP collected less than 7 days apart. Linear regression analysis was used to construct a prediction model for 24hUP with uACR as the primary predictor. Possible confounders (age, gender, body mass index, morning versus afternoon spot urine collection, estimated glomerular filtration rate) for the primary relationship between uACR and 24h UP were evaluated in the model. We used receiver operating characteristic (ROC) analysis to identify the best uACR cutoff to predict significant proteinuria (defined as a 24hUP > 500mg). Results: We included 665 patients, with a median age of 66 years (IQR 59-72). The spot urine was collected in the morning (before 1200 hours) in 382 (57%) patients, and in the afternoon in 283 (43%) patients. The median 24hUP was 321 (IQR 129-2512.5) mg, median uACR was 107 (IQR 13.5-1845) mg/g, and median serum creatinine was 1.2 (IQR 1-1.8) mg/dL. The uACR correlated well with 24h UP (Pearson’s r= 0.83, 95% CI 0.80-0.85). Linear regression showed that E (24h UPi) = 362 + 1.05(uACRi), and this model was statistically and clinically significant (p < 0.001 and R2 of 0.68, respectively). Age, gender, body mass index, eGFR, and time of day of spot urine collection did not confound the primary relationship between uACR and 24hUP, and no collinearity was observed. A uACR cutoff of > 280 mg/g was the best predictor of a 24hUP > 500 mg (area under the ROC curve 0.98, sensitivity 92%, specificity 97%). For simplicity, we assessed the predictive value of uACR > 300 mg/g for 24h UP > 500 mg. Among patients with 24huACR > 300 mg/g 264 (96%) had a 24hUP > 500 mg, and 31 (7%) of patients with uACR < 300 mg/g had a 24h UP > 500 mg (p < 0.001). Conclusions: In systemic AL amyloid patients, we showed that uACR on a random urine sample correlated well with 24h UP, and can be used to estimate proteinuria with a linear regression model. Based on these findings, and the convenience of uACR testing for patients, we propose that uACR should be used to monitor renal response to AL amyloidosis therapy.
PrE0505: Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (MPM)—A PrECOG LLC study.
Authors: Forde Patrick M. , Sun Zhuoxin , Anagnostou Valsamo , Kindler Hedy L. , Purcell William T. , Goulart Bernardo H. L. , Dudek Arkadiusz Z. , Borghaei Hossein , Brahmer Julie R. , Ramalingam Suresh S.
Published: May 2020

9003

Background: First-line CP was FDA-approved in 2004 for unresectable MPM. Given the role of inflammation in MPM and promising responses to PD-1 pathway blockade in pretreated MPM, we conducted a phase 2 single arm study of the anti-PD-L1 antibody, durvalumab (durva), combined with CP for patients (pts) with untreated MPM of any subtype. Methods: Eligible pts were treatment-naïve with surgically unresectable MPM. Primary endpoint was overall survival (OS); pts received up to 6 cycles of durva-CP, followed by maintenance durva up to 1 year. Carboplatin was permitted for pts with baseline hearing or renal impairment. The first 15 pts were monitored for dose-limiting toxicities (DLTs). Secondary endpoints included toxicity, objective response by modified RECIST, progression-free survival (PFS), and correlative analyses. With a sample size of 55 patients and 32 events, the study had 90% power to detect a 58% improvement in median OS from 12 months (m) (historical control) to 19 m with durva-CP. Results: PrE0505 enrolled 55 patients at 15 US-based sites between 06/2017 and 06/2018. Histologic subtypes were epithelioid (75%), biphasic (11%), sarcomatoid (13%), and desmoplastic (2%). There were no DLTs during the run-in period. As of January 2020 the median follow up is 20.6 m and 29 deaths have occurred. The median OS at the time of report is 21.1 m. The 12 m OS rate was 70% with a 2 sided 95% confidence interval (56%, 81%) and two-sided 80% CI (62%, 78%). Analyses for the secondary endpoints were ongoing at abstract submission. Exome sequencing, TCR sequencing and dual PD-L1/CD8 staining have been completed on baseline tumors from at least 45 of the 55 patients enrolled as well as RNA sequencing for those with adequate tissue. Initial results show that tumors harbored an average tumor mutation burden of 22 somatic sequence alterations and varying levels of aneuploidy were detected. Conclusions: The combination of chemotherapy with durvalumab delivered a promising median OS for previously untreated pts with unresectable MPM. Full results from the study along with the extensive correlative analyses performed will be reported. The phase 3 PrE0506/DREAM3R trial evaluating CP-durvalumab versus CP alone will commence enrollment in the United States and Australia in 2020. Clinical trial information: NCT02899195.
Randomized phase II study on gemcitabine with or without ramucirumab as second-line treatment for advanced malignant pleural mesothelioma (MPM): Results of Italian Rames Study.
Authors: Pagano Maria , Ceresoli Giovanni Luca , Zucali Paolo Andrea , Pasello Giulia , Garassino Marina Chiara , Grosso Federica , Tiseo Marcello , Soto Parra Hector J. , Zanelli Francesca , Cappuzzo Federico , Grossi Francesco , de Marinis Filippo , Pedrazzoli Paolo , Gnoni Roberta , Bonelli Candida , Berselli Annalisa , Boni Luca , Normanno Nicola , Pinto Carmine
Published: May 2020

9004

Background. The RAMES Study (EudraCT Number 2016-001132-36) is a multicenter, double-blind, randomized phase II trial exploring the efficacy and the safety of the addition of ramucirumab to gemcitabine as the second-line treatment in MPM patients (pts) after platinum/pemetrexed regimens. Methods. The pts were assigned (1:1) to receive Gemcitabine 1000 mg/m2 i v on days 1 and 8 every 21 days with Placebo (Arm A) or Ramucirumab 10 mg/kg i v on day 1, of a 21-day cycle (Arm B), until tolerability or progressive disease. Pts was stratified by ECOG/PS (0-1 vs 2), age (≤ 70 vs > 70 yrs), histology (epithelioid vs non-epithelioid) and time to progression (TTP) after first-line therapy. The primary endpoint was overall survival (OS). Assuming a proportion of OS equal to 40% at 1 year in arm A, a 12% absolute improvement in OS at 1 yrs was expected in Arm B (hazard ratio = 0.70).114 events (156 subjects) are required for a one-sided log-rank test with α = 0.15 to have 80% power. Results. From December 2016 to July 2018, 164 pts were randomized, 81 pts in Arm A and 80 Arm B; 3 pts were randomized but not treated. Characteristics of pts were: median age 69 yrs (44-81), males 119 (73.9%), females 42 (26.1%); ECOG/PS0 96 (59.6%) ECOG/PS1-2 65 (40.4%); histotype epithelioid 132 (81.9%), non-epithelioid 29 (18.1%); stage III 98 (60.7%), stage IV 60 (37.3%), 3 (2.0%) missing; asbestos exposure assessed 80 (49.7%). Median of courses was 3.50 in Arm A and 7.50 in Arm B. OS was significantly longer in Arm B with median 13.8 mths (70% CI 12.7-14.4) vs Arm A with 7.5 mths (70% CI 6.9-8.9), HR 0.71 (70% CI 0.59-0.85, p = 0.057). OS at 6 and 12 mths was in Arm A 63.9% and 33.9%, and in Arm B 74.7% and 56.5%, respectively. In Arm B OS was not correlated to TTP at first-line therapy (13.6 mths in TTP ≤6 mths and 13.9 mths in TTP > 6 mths) and histotypes (13.8 months in the epithelioid and 13.0 months in non-epithelioid). No significant differences in thromboembolism G3-4 events were observed in Arm A vs Arm B (p= 0.64). None hypertension G3-4 was reported in Arm A vs 5 pts (6.3%) in Arm B (p= 0.022). No significant differences in G3-4 haematological toxicities between the two arms were reported. Conclusion: In the RAMES Study the addition of Ramucirumab to Gemcitabine significantly improved OS regardless of age of pts, tumor histotype and TTP at the first-line treatment. Gemcitabine plus Ramucirumab can be considered a manageable regimen in second-line treatment of advanced MPM pts. Clinical trial information: NTC03560973.
A phase II trial of atezolizumab and bevacizumab in patients with relapsed/refractory and unresectable malignant peritoneal mesothelioma.
Authors: Raghav Kanwal Pratap Singh , Overman Michael J. , Liu Suyu , Willett Anneleis , Royal Richard Eldon , Malpica Anais , Scally Christopher , Wistuba Ignacio Ivan , Futreal Andrew , Mahvash Armeen , Yun Cindy , Dervin Shannon , Mckenna Edward Francis , Schulze Katja , Hwu Patrick , Yao James C. , Kopetz Scott , Varadhachary Gauri Rajani , Halperin Daniel M.
Published: May 2020

9013

Background: Malignant peritoneal mesothelioma (MPeM) is an orphan malignancy. No recommended/FDA approved therapies exist for salvage treatment beyond first-line platinum and pemetrexed based chemotherapy. While immune checkpoint inhibition has shown preliminary efficacy in mesotheliomas, data and efficacy is limited in MPeM patients (pts) [objective response rate (ORR) ~ 11%; median progression-free survival (mPFS) ~ 4 months (m); median overall survival (mOS) ~ 11 m]. We aimed to prospectively assess the safety and efficacy of combined anti-PD1 (atezolizumab) and VEGF (bevacizumab) blockade (AtezoBev) in pts with MPeM. Methods: In this phase 2 study, eligible pts with histologically confirmed MPeM, ECOG PS 0-1, and prior platinum and pemetrexed treatment were treated with 1200 mg of atezolizumab and 15 mg/kg of bevacizumab IV every 21 days until disease progression, unacceptable toxicity, or withdrawal. Primary endpoint was confirmed ORR by RECIST 1.1 by independent radiology review. Duration of response (DOR), PFS and OS were pre-specified secondary endpoints. Results: Among 20 enrolled pts (3/2017 - 2/2019), median age was 63 (range, 33-87) years, 12 (60%) were female, 12 (60%) had PS 0, and 2 (10%) had biphasic MPeM. Among 20 evaluable pts (median cycles 14), confirmed ORR was 35% (7 pts; 95% CI: 15.4-59.2) (median DOR 8.8 m). Responses were ongoing in 5/7 (71.4%) pts at data cutoff. The median follow-up was 20.5 months. Six deaths were observed during follow-up, and the 1-year OS was 79% (95% CI: 52 – 91) (median OS ~ NR). Median PFS was estimated as 17.6 m (95% CI: 9.1 – NR). The 1-year PFS was 54% (95% CI: 28 – 74). Grade 3 (no grade 4/5) treatment-emergent adverse events occurred in 10 (50%) pts; most common being hypertension (40%) and anemia (10%). Two (10%) pts had grade 3 immune-related adverse events. Translational studies are ongoing. Conclusions: AtezoBev showed promising and durable efficacy in relapsed/refractory MPeM with acceptable safety profile. Ongoing multiomic analyses of pre and on-treatment tissue/liquid biopsies obtained on all these pts will provide additional insight into mechanisms and biomarkers of response and resistance. Clinical trial information: NCT03074513.
PIT-1: Randomized phase II trail of pemetrexed-cisplatin plus bevacizumab or concurrent thoracic radiation therapy followed by surgery in stage IIIA (N2) nonsquamous non-small cell lung cancer.
Authors: Takamochi Kazuya , Suzuki Kenji , Tsuboi Masahiro , Niho Seiji , Ishikura Satoshi , Oyamada Shunsuke , Yamaguchi Takuhiro , Yoshino Ichiro , Ito Hiroyuki , Okumura Norihito , Tanaka Fumihiro , Saji Hisashi , Tsuchida Masanori , Horio Hirotoshi , Shiono Satoshi , Matsuura Motoki , Ikeda Norihiko , Tanaka Toshiki , Okada Morihito
Published: May 2020

9014

Background: PIT-1 (Personized Induction Therapy-1) is a multicenter, open-label, randomized phase II study using selection design of platinum doublet chemotherapy plus angiogenesis inhibitor or concurrent thoracic radiation therapy (TRT) as induction therapy followed by surgery in patients with stage IIIA (N2) nonsquamous non-small cell lung cancer (NSCLC) to investigate the efficacy and safety of these treatment strategies. Methods: Patients with stage IIIA (pathologically proven N2) nonsquamous NSCLC randomly received (1:1) induction therapy consisting of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) plus bevacizumab (15 mg/kg) intravenously every 3 weeks for three cycles (arm A) or concurrent TRT (45 Gy in 25 fractions) (arm B) followed by surgery. The primary endpoint was 2-year progression-free survival (PFS) rate and key secondary endpoints included overall survival (OS), the objective response rate (ORR) as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, the pathological complete remission (pCR) rate, feasibility and toxicity. Results: Eighty-eight patients were randomly assigned (each arm, n = 44) between October 2013 and June 2017 and 82 (arm A, n = 42; arm B, n = 40) were treated. Patient demographics were balanced between the two arms. The percentage of patients who received induction therapy followed by surgery was 88.1% (37/42) in arm A and 92.5% (37/40) in arm B. The complete resection rate was 81.1% (30/37) in arm A, and 91.9% (34/37) in arm B. The 2-year PFS rate was 36.8% (95% CI: 22.4-51.2) in arm A, and 50.0% (95% CI: 33.8-64.2) in arm B. The 2-year OS rate was 80.5% (95% CI: 64.7-89.7) in arm A, and 80.0% (95% CI: 64.0-89.5) in arm B. The ORR was 50.0% (21/42) in arm A and 60.0% (24/40) in arm B. The pCR rate was 8.1% (3/37) in arm A and 10.8% (4/37) in arm B. Grade 3 or 4 toxicities occurred during induction therapy in 35.7% of the patients in arm A and 22.5% of the patients in arm B. Grade 3 or 4 surgical complications occurred in 21.4% of the patients in arm A and 20.0% of the patients in arm B. Although no fatal toxicity was observed during induction therapy in either arm, two patients in arm A died after surgery due to bronchopleural fistula. Conclusions: The 2-year PFS rate in arm B was higher than that in arm A. Fatal surgical complications were only observed in arm A. Therefore, we chose pemetrexed-cisplatin plus concurrent thoracic radiation therapy as the investigational induction treatment strategy for a future phase III study. Clinical trial information: 000011941.
Reliable detection of the presence of pulmonary carcinoma on whole-slide images by a deep learning model.
Authors: Toyokawa Gouji , Kanavati Fahdi , Momosaki Seiya , Rambeau Michael , Kozuma Yuka , Shoji Fumihiro , Yamazaki Koji , Takeo Sadanori , Iizuka Osamu , Tsuneki Masayuki
Published: May 2020

9025

Background: Lung cancer is one of the leading causes of cancer-related death worldwide, and its histopathological diagnosis is crucial for deciding on optimum treatment strategies. Recently, artificial intelligence (AI) models have been widely shown to be useful in various medical fields, particularly image and pathological diagnoses; however, AI models for the pathological diagnosis of pulmonary lesions that have been validated in large-scale test sets are yet to be seen. Methods: We trained a convolution neural network based on the Efficient Net B3 architecture to classify carcinoma from whole slide images (WSIs) using a training dataset of 3640 images. WSI diagnoses were available. We used a transfer learning approach, in which the starting weights were obtained from a pre-trained model on ImageNet. The model was then trained on our dataset using multiple instance learning, a semi-supervised learning approach. To classify a WSI, the model was applied in a sliding window fashion with an input tile size of 512x512 and a stride of 256. The maximum probability was then used as a WSI diagnosis. Results: We evaluated our model on a total of 2680 WSIs originating from five independent sources (two hospitals in Japan and three public datasets from around the world). The model achieved a Receiver Operator Curve Area Under the Curves (ROC AUCs) of 0.974, 0.974, 0.996, 0.988, and 0.981, respectively. Conclusions: We successfully established a reliable AI model for differentiating between lung carcinoma and non-neoplasm with a high ROC AUC on five independent test sets. If used in clinical practice, our model could help reduce the burden on pathologists and be useful for diagnosing pulmonary lesions in areas in which there are shortages of pathologists. Further prospective multicenter studies are warranted in order to validate the results obtained in the current study.
Role of T0 status in overall survival for unresectable stage III non-small cell lung cancer.
Authors: Komiya Takefumi , Powell Emily , Vu Charles , Guddati Achuta Kumar
Published: May 2020

9026

Background: Occult (T0) primary non-small cell lung cancer (NSCLC) with mediastinal involvement is a known but rare clinical condition. Its prognosis has not been evaluated well in the literature. Methods: Using National Cancer Database (NCDB), cases diagnosed between 2004 and 2016 with unresectable clinical stage III NSCLC with N2 or N3 involvement were selected and assigned to T0 or T1-4 group according to AJCC staging version 6th or 7th. Clinical demographics including use of chemotherapy/immunotherapy in first course of treatment were collected. As validation, independent data using Surveillance, Epidemiology, and End Results Program (SEER) was analyzed accordingly. Survival analyses were conducted using Kaplan-Meier and log-rank tests. Results: A total of 458 and 84,263 cases met criteria for unresectable, N2/N3 stage III NSCLC with T0 and T1-4 status, respectively. T0 status was associated with younger age, recent diagnosis, adenocarcinoma histology, N3, and use of chemotherapy. Overall survival (OS) was improved in T0 over T1-4 group (p < 0.0001) with a five-year survival rate of 30.5% and 12.7%, respectively, with a validation with multivariate proportional hazard models. Propensity score matching analyses using all 458 patients in each group demonstrated a significant difference in OS (p < 0.0001). The difference was also significant in a subset of those who have undergone chemoradiation (p < 0.0001). Independent analysis using SEER data confirmed its superior survival of T0 over T1-4 with a five-year survival rate of 35.3% and 13.5%, respectively. Conclusions: Both NCDB and SEER analyses demonstrated better survival of T0 than T1-4 counterpart in the setting of unresectable stage III NSCLC, irrespective of chemotherapy status. This group may require a distinct assignment to new staging group after further investigation.
Prognostic role of mid-treatment PET/CT and plasma cytokines in patients undergoing chemoradiation for locally advanced non-small cell lung cancer (LA-NSCLC).
Authors: Zeng Jing , Rengan Ramesh , Baik Christina S , Eaton Keith D. , Goulart Bernardo H. L. , Lee Sylvia , Martins Renato G. , Santana-Davila Rafael , Hippe Daniel S , Lampe Paul D. , Houghton A. McGarry , Vesselle Hubert , Kinahan Paul , Bowen Stephen R.
Published: May 2020

9040

Background: Patients with unresectable LA-NSCLC are treated with concurrent chemoradiation (CRT) and consolidation immunotherapy with survival that range from months to years or even decades. Early predictive biomarkers have potential to identify patients who are unlikely to benefit from continuing standard of care therapy and require a change in management. We investigated biomarkers that are widely available (PET/CT scan and plasma cytokine levels) to develop early predictors (mid-CRT) of survival in a phase II clinical trial of chemoradiation for LA-NSCLC. Methods: 37 Patients with AJCC v7 stage IIB-IIIB NSCLC were prospectively enrolled on the FLARE-RT trial (NCT02773238) from 2016-9. All patients underwent chemoradiation; 18 also received adjuvant durvalumab. PET/CT exams were performed at week 3 of CRT and response status was pre-defined by published metrics. 21 patients consented to peripheral blood collection at baseline and week 3, and plasma levels of 43 common inflammatory cytokines were measured. Bootstrapping over 100 iterations of the least absolute shrinkage and selection operator (LASSO) was performed to reduce feature dimensionality and guard against false discoveries. Cox regression of selected cytokine levels and PET response status, as well as time-dependent receiver-operating characteristic (ROC) analysis, were evaluated for associations to overall survival (OS). Results: Median follow-up was 18 months with 1-year OS 81% and PFS 52%. Mid-CRT PET response (as determined by pre-defined metrics) was strongly associated with OS (HR 5.6 [1.4-22.0], p = 0.015) after adjusting for radiation target volume, with 1-yr OS 94% for responders vs. 68% for non-responders (p = 0.017). Plasma TNFα level was also prognostic for OS (HR 1.9 [1.1-3.5], p = 0.030). TNFα retained significance for OS (HR 2.3 [1.2-4.6], p = 0.016) after adjusting for PET response. Bivariate mid-CRT PET response and TNFα generated a parsimonious model to predict OS (AUC = 0.85, 18-month horizon). Conclusions: Risk stratification for long-term survival after chemoradiation in patients with LA-NSCLC may be achievable based on mid-chemoradiation assessment of widely available biomarkers (PET imaging and plasma TNFα level). Combined functional imaging and peripheral blood biomarkers will be validated in a larger sample of our trial cohort, along with other independent patient populations. Clinical trial information: NCT02773238.
Peripheral blood T-cell receptor immune repertoire characterization of resectable stage IIIA non-small cell lung cancer patients receiving neo-adjuvant chemo-immunotherapy treatment from NADIM study.
Authors: Cruz Bermudez Alberto , Casarrubios Marta , Laza Briviesca Raquel , Sierra-Rodero Belen , Barquin Miguel , Romero Atocha , Franco Fernando , Calvo Virginia , Nadal Ernest , Insa Amelia , Garcia-Campelo Rosario , Casal Joaquin , Domine Manuel , Massuti Bartomeu , Majem Margarita , Rodriguez-Abreu Delvys , Martinez-Marti Alex , De Castro Javier , Provencio-Pulla Mariano
Published: May 2020

9041

Background: Characterization of the peripheral blood T-cell receptor (TCR) repertoire has become a novel approach to predict the clinical benefit to anti-PD1/PDL1 therapy. However, there is lack of knowledge about the clinical relevance of TCR repertoire in terms of pathological response and clinical outcomes (PFS and OS) in chemo-immunotherapy. To answer this question we have analysed samples from the NADIM study (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant chemo-immunotherapy with Nivolumab. Methods: Using ION Torrent-based next-generation sequencing we have analysed TCR repertoire of peripheral blood from 30 patients receiving chemo-immunotherapy. Using 25ng of total RNA from PBMCs, clonal convergence, evenness and diversity were calculated at diagnosis (pre-treatment) and after 3 cycles of Nivolumab plus carboplatin (post-treatment). Regarding pathological responses, patients were classified in 3 groups: complete response (pCR) (0% viable tumour at the resection specimen), mayor response (pMR) ( < 10% viable tumour) and incomplete response (pIR) ( > 10% of viable tumour). At data analysis, PFS and OS median follow-up times were longer than 20 months. Results: No statistically significant differences in TCR repertoire in terms of evenness (p = 0,373), diversity (p = 0,691) or convergence (p = 0,054) between pre- and post-neoadjuvant treatment were observed. Similarly, no significant differences were observed in these metrics between pathological response groups. However, a detailed analysis of the clones showed that the percentage of frequent clones (greater than 0.1%) that increase after neoadjuvant therapy does show differences between the different pathological response groups (pIR vs pMR), being elevated in patients who presented responses greater than 90% (p = 0.0385). Regarding the clinical benefit, having this parameter higher than the median (43,90% in this cohort) is associated with a higher PFS (p = 0.0490) and OS (p = 0.078) using KM Log-rank test. Conclusions: Evenness, Diversity and Convergence derived from immune repertoire analysis do not appear to be clinically useful in the context of neoadjuvant chemo-immunotherapy in lung cancer. However, the detailed analysis of the clones seems promising. The increase of the most frequent clones after treatment seems to be associated to different clinical variables such as pathological response and PFS in these patients. Clinical trial information: NCT03081689.
Efficacy and safety of nivolumab for malignant mesothelioma in the real world.
Authors: Mikami Koji , Yokoi Takashi , Takahashi Ryo , Shibata Eisuke , Niki Maiko , Nakajima Yasuhiro , Negi Yoshiki , Ishigaki Hirotoshi , Tada Akio , Higashiyama Tomoki , Kamei Takao , Minami Toshiyuki , Kuribayashi Kozo , Kijima Takashi
Published: May 2020

9052

Background: Until recently, the standard treatment for advanced malignant pleural mesothelioma (MPM) was only cisplatin plus pemetrexed. Nivolumab, an anti-programmed death-1 monoclonal antibody, shows efficacy against pretreated MPM and has been approved in Japan, but the data regarding the efficacy and safety of nivolumab in MPM are limited to those from a small number of patients of the MERIT study. Therefore, it is important to accumulate real-world data on the efficacy and safety of nivolumab for MPM. Methods: We retrospectively analyzed all patients with MPM who received nivolumab at Hyogo College of Medicine Hospital from August 2018 to December 2018. Results: A total of 77 patients (61 males and 16 females) were included. There were 62, 10, and 5 patients with performance statuses of 0–1, 2, and 3, respectively. There were 63, 8, and 6 patients with epithelioid, sarcomatoid, and bi-phasic histologies, respectively. Nivolumab was administered as second-, third-, and ≥fourth-line treatment to 48, 15, and 11 patients, respectively. In 66 patients who were examined for efficacy, the response rate (RR) was 24.2% and the disease control rate (DCR) was 63.6%. By the histology type, the RR and DCR were 15.1% and 62.3% for the epithelioid type, 62.5% and 87.5% for the sarcomatoid type, and 20.0% and 40.0% for the bi-phasic type, respectively. The median progression-free survival (mPFS) was 4.1 months and the median overall survival (mOS) was 13.3 months. Analyzing the efficacy based on the neutrophil-to-lymphocyte ratio (NLR) in the peripheral blood, the RRswere 14.7% in the NLR≥3.5 group and 25.8% in the NLR < 3.5 group. The mPFS and mOS in the NLR≥3.5 group were 3.1 months and 11.4 months, respectively,whereas those in the NLR < 3.5 group were 5.6 months and not reached, respectively. There were no significant differences in the RR, PFS, and OS between the groups, but a trend of better RRs and longer survivals wasobserved in the NLR < 3.5 group than in the NLR≥3.5 group. Regarding adverse events, fatigue (grades 1−2) was observed in 8, hypothyroidism (grade 1–2) in 11, renal dysfunction (grade 1–3) in 6, loss of appetite (grade 1–2) in 2, pneumonitis (grade 3) in 1, rash (grade 1) in 2, and hypopituitarism (grade 3) in 1 patient(s). Conclusions: This retrospective study revealed the effectiveness and safety of nivolumab for MPM in the real-world setting.Nivolumab can be used as a standard second-line treatment for MPM. Furthermore, it has been suggested that the NLR may be a predictive marker of the effect of nivolumab for MPM, as pointed out in other carcinomas.
Carboplatin versus cisplatin for the treatment of extensive-stage small cell lung cancer (SCLC): A National VA Database analysis.
Authors: Azar Ibrahim , Austin Adam , Kim Seongho , Jang Hyejeong , Chopra Amit , Mehdi Syed Arzoo , Mamdani Hirva
Published: May 2020

9061

Background: Current standard of care first line treatment for extensive stage SCLC includes combination of platinum-etoposide doublet with an immune checkpoint inhibitor. Carboplatin is preferred over cisplatin in the extensive stage disease because of its favorable toxicity profile. Data comparing the efficacy of carboplatin with cisplatin in the metastatic setting are limited. Methods: Data from the National VA Cancer Cube database were compiled. Only pathologically confirmed cases of extensive stage SCLC that received platinum-based multiagent chemotherapy were included. Interval-censored Weibull and Cox proportional hazard regression models were used to estimate median overall survival (OS) and hazard ratio (HR), respectively. Two survival curves were compared by a Wald test. Results: Overall, 2600 SCLC cases were studied: 1968 received carboplatin-based therapy (Carbo-SCLC) while 632 received cisplatin-based therapy (Cis-SCLC). Median OS of Carbo-SCLC and Cis-SCLC was 0.71 years (95% CI 0.68-0.75) versus 0.70 years (95% CI 0.64-0.76), respectively (HR = 0.99; 95% CI 0.90-1.10; p = 0.90). Median OS of patients with ECOG-PS of 0, 1, 2 and 3 was similar for Carbo-SCLC and Cis-SCLC. HR of death for Carbo-SCLC compared to Cis-SCLC stratified by performance status were: ECOG-PS 0: 1.04 (95% CI 0.78-1.38; p = 0.80); ECOG-PS 1: 0.87 (95% CI 0.71-1.06; p = 0.17); ECOG-PS 2: 0.92 (95% CI 0.69-1.24; p = 0.6); ECOG- PS 3: 1.13 (95% CI 0.66-1.92; p = 0.66). Multivariable regression analysis accounting for age and ECOG-PS shows a HR of 0.92 (95% CI 0.80-1.05; p = 0.24). Conclusions: Cisplatin-based chemotherapy was not associated with a survival advantage over carboplatin-based chemotherapy in extensive-stage SCLC., including in patients with robust performance status and young patients. The findings from this large dataset along with the favorable toxicity profile of carboplatin support its use as the platinum agent of choice in extensive stage SCLC.
Treatment strategies for thymic carcinoma in a real-life setting: Insights from the rythmic network.
Authors: Girard Nicolas , Petat Arthur , Dansin Eric , Fabien Calcagno , Greillier Laurent , Pichon Eric , Kerjouan Mallorie , Clément Duchene Christelle , Mennecier Bertrand , Westeel Virginie , Thillays Francois , Quantin Xavier , Ginoux Marylise , Oulkhouir Youssef , Thiberville Luc , Ricordel Charles , Molina Thierry , Fournel Pierre , Bigay-Game Laurence , Besse Benjamin
Published: May 2020

9072

Background: Thymic carcinomas are an aggressive and difficult to treat subset of thymic epithelial tumors (TETs) that represent a heterogeneous group of rare intrathoracic malignancies. Most of the current knowledge and guidelines tumors rely on surgically-oriented databases focusing on early-stage disease, and small prospective, single-arm trials conducted in metastatic thymic carcinomas, mostly in a refractory, late-line setting. “Réseau tumeurs THYMiques et Cancer” (RYTHMIC) is the nationwide network for TETs in France. The management of any patient has to be systematically discussed on a real-time basis at a national multidisciplinary tumor board; a database is hosted by the French Thoracic Cancer Intergroup (IFCT). Methods: We took advantage of the RYTHMIC prospective database to describe baseline characteristics, analyze treatment strategies, and provide landmark outcomes in a cohort of consecutive patients with thymic carcinoma. The inclusion period was January 2012 to April 2017. Results: A total of 213 patients were analyzed. Overall, 60 (28%) patients were considered as surgical candidates upfront, 91 (43%) received primary chemotherapy, and 62 (29%) received exclusive chemotherapy. Median OS was 49.2 months (IC95%: 34.8-63.6); OS was significantly longer in patients with a lower stage at diagnosis (p < 0.001), who were operated on upfront, as opposed to patients who received primary or exclusive chemotherapy (p < 0.001). Surgery, conducted upfront or after primary chemotherapy, was significantly associated with more prolonged OS (p < 0.001); complete resection and postoperative radiotherapy were also predictors of better outcome (p = 0.018 and p = 0.081, respectively). Exclusive chemotherapy was delivered to 62 patients with advanced disease, who all received platinum-based regimen as first-line treatment; PAC regimen was delivered to 66% of patients. Best objective response to first-line chemotherapy was partial response in 33 (53%) patients. Median PFS was 8.0 months (IC95%: 5.0-11.1). Median OS was 32.9 months (IC95%: 20.6-45.1). Response to first-line chemotherapy and squamous histology were the only significant predictors of OS (p = 0.002 and p = 0.040, respectively). Conclusions: Our cohort is the first to analyze in depth outcomes and treatment strategies in a prospective cohort of consecutive patients with thymic carcinoma. While we confirm the major prognostic impact of surgery, our data highlight the need for optimized multidisciplinary management and innovative therapies as the survival of patients remains limited.
Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE).
Authors: Rodriguez-Abreu Delvys , Johnson Melissa Lynne , Hussein Maen A. , Cobo Manuel , Patel Anjan Jayantilal , Secen Nevena Milica , Lee Ki Hyeong , Massuti Bartomeu , Hiret Sandrine , Yang James Chih-Hsin , Barlesi Fabrice , Lee Dae Ho , Paz-Ares Luis G. , Hsieh Robert Wenchen , Miller Karen , Patil Namrata , Twomey Patrick , Kapp Amy V. , Meng Raymond , Cho Byoung Chul
Published: May 2020

9503

Background: The immunomodulatory receptor TIGIT is a novel inhibitory immune checkpoint present on activated T cells and NK cells in multiple cancers, including NSCLC. In a phase I study (GO30103), co-inhibition of TIGIT and PD-L1 signaling with tira plus atezo in CIT-naïve PD-L1 positive NSCLC potentially improved overall response rates (ORR) compared to historical ORR with PD-L1/PD-1 inhibitors. We conducted this phase II trial to confirm the efficacy and safety of tira plus atezo (TA) compared to placebo plus atezo (PA) in 1L NSCLC (GO40290, NCT NCT03563716). Methods: This prospective, randomized, double-blind, placebo-controlled trial enrolled patients (pts) with chemotherapy-naïve PD-L1+ (TPS ≥ 1% by 22C3 IHC pharmDx Dako assay) locally advanced or metastatic NSCLC with measurable disease, ECOG PS 0-1, and without EGFR or ALK alterations. Pts were randomized 1:1 to TA (tira 600 mg IV plus atezo 1200 mg IV) or PA (placebo plus atezo 1200 mg IV) on day 1 of every 3-week cycle. Stratification factors were PD-L1 status (TPS ≥ 50% vs TPS 1-49%), histology, and tobacco history. Co-primary endpoints were investigator assessed ORR and PFS, and additional endpoints were duration of response (DOR), OS, and safety. Exploratory endpoints were the effect of PD-L1 status on ORR and PFS. Results: 135 pts were randomized to PA (n = 68) or TA (n = 67). At primary analysis (30 Jun 2019), TA improved ORR and median PFS (mPFS) compared to PA, with median follow-up of 5.9 mo. In the safety population (68 in PA, 67 in TA), treatment-related AEs (TRAEs) occurred in 72% (PA) and 80.6% (TA); Grade ≥3 TRAEs occurred in 19.1% (PA) and 14.9% (TA). AEs leading to treatment withdrawal occurred in 10.3% (PA) and 7.5% (TA). Clinical trial information: NCT03563716 . With an additional six months of follow-up since the primary analysis (2 Dec 2019, median follow-up of 10.9 mo), improvement in ORR and mPFS was maintained in ITT for TA (37.3% [25.0, 49.6] and 5.6 mo [4.2, 10.4]) vs PA (20.6% [10.2, 30.9] and 3.9 mo [2.7, 4.5]). The safety profile remained tolerable. Conclusions: Treatment with TA compared to PA showed clinically meaningful improvement in ORR and PFS in ITT. The safety profile of TA was similar to PA. [Table: see text]
Concurrent osimertinib plus gefitinib for first-line treatment of EGFR-mutated non-small cell lung cancer (NSCLC).
Authors: Rotow Julia K , Costa Daniel Botelho , Paweletz Cloud P. , Awad Mark M. , Marcoux Paul , Rangachari Deepa , Barbie David Allen , Sands Jacob , Cheng Michael L. , Johnson Bruce E. , Oxnard Geoffrey R. , Jackman David Michael , Kwiatkowski David J. , Kehl Kenneth L. , Izdebski Monika D , Lau Christie J. , Vasquez Kevin A , Janne Pasi A.
Published: May 2020

9507

Background: First-line treatment with an EGFR tyrosine kinase inhibitor (TKI) is standard of care for patients (pts) with EGFR-mutated NSCLC. The EGFR TKI osimertinib is active against the acquired gefitinib-resistant mutation EGFR T790M, as is gefitinib against the osimertinib-resistant EGFR C797S. Preclinical evidence suggests dual EGFR inhibition with gefitinib + osimertinib may delay emergence of acquired resistance. Methods: This ongoing phase I/II study enrolled pts with stage IV EGFR-mutated (L858R or del19) NSCLC, without prior therapy for metastatic disease. Treatment in dose escalation (n = 6): concurrent osimertinib 40 mg or 80 mg + gefitinib 250 mg daily. In dose expansion (n = 21): osimertinib + gefitinib at the maximum tolerated dose (MTD). Prior to protocol amendment 6 pts received alternating monthly cycles of TKI monotherapy and were excluded from this analysis. The primary endpoints in the dose escalation and expansion phases were, respectively, identification of the MTD and feasibility, defined as receipt of combination therapy for ≥ 6 four-week cycles. Secondary endpoints included overall response rate (ORR), survival outcomes, plasma EGFR mutation clearance (cell free DNA by droplet digital PCR (ddPCR)), and mechanisms of acquired resistance. Results: From May 2017 to July 2019 27 pts were enrolled and evaluable for the primary endpoints. The MTD was osimertinib 80 mg plus gefitinib 250 mg orally daily. In feasibility analysis, 81.5% completed ≥6 cycles combination therapy (1 pt discontinued for progression, 4 for toxicity). The ORR was 85.2% (95% CI 67.5%-94.1%). Best response: 85.2% partial response, 14.8% stable disease. The most common treatment-related adverse effects (TRAEs) (% any grade, % grade 3) were rash (96.3%, 3.7%), diarrhea (85.2%, 11.1%) and dry skin (70.4%, 0%). Plasma ddPCR (n = 25 pts) detected the driver EGFR mutation at baseline in 68% of pts. In these pts, plasma EGFR cleared to undetectable at 2 weeks treatment in 82.4%. At 14.8 months median follow up the median progression free survival was not yet reached. Conclusions: Combination therapy with osimertinib and gefitinib is tolerable for first-line treatment of EGFR-mutated NSCLC and resulted in rapid plasma clearance of the EGFR mutation. The observed ORR is consistent with previously reported first-line response rates to osimertinib. Analysis of survival outcomes and acquired resistance mechanisms are pending data maturity and will facilitate understanding of the role of first-line dual EGFR TKI therapy for this pt population. Clinical trial information: NCT03122717 .
Capmatinib in patients with high-level MET-amplified advanced non–small cell lung cancer (NSCLC): results from the phase 2 GEOMETRY mono-1 study.
Authors: Wolf Juergen , Overbeck Tobias R. , Han Ji-Youn , Hochmair Maximilian , de Marinis Filippo , Ohashi Kadoaki , Smit Egbert F. , Power Danielle , Garon Edward B. , Groen Harry J.M. , Tan Daniel Shao-Weng , Waldron-Lynch Maeve , Le Mouhaer Sylvie , Nwana Ngozi , Giovannini Monica , Heist Rebecca Suk
Published: May 2020

9509

Background: In the ongoing, multicohort, phase 2 GEOMETRY mono-1 study, capmatinib (INC280) has shown efficacy in METex14–mutated NSCLC patients (pts) who were pretreated (cohort 4) or treatment (tx)-naïve (cohort 5b). Here, we report the efficacy and safety of capmatinib in pts with high-level MET-amplified (gene copy number [GCN] ≥10) advanced NSCLC who were either pretreated with 1 or 2 prior lines of systemic therapy (cohort 1a) or tx-naïve (cohort 5a). Methods: Adult pts (≥18 years), ECOG PS 0–1 who had ALK and EGFR wt, stage IIIB/IV (any histology) MET-amplified NSCLC with GCN≥10 received capmatinib 400 mg twice daily (fasting). Primary and key secondary endpoints were overall response rate (ORR) and duration of response (DOR), respectively, by blinded independent review committee (BIRC) assessment per RECIST v1.1. Other secondary endpoints included investigator-assessed ORR, DOR, disease control rate (DCR), progression-free survival (PFS, BIRC and investigator assessment), overall survival, and safety. Results: As of Jan 06, 2020, 84 pts were evaluable for efficacy (cohort 1a [2nd/3rd line], 69 pts; Cohort 5a [1st line], 15 pts). Tx was ongoing for 3 pts in cohort 1a, none in cohort 5a. Per BIRC assessment in cohorts 1a and 5a, respectively, ORR was 29% and 40%, median DOR was 8.31 months (mo, 20 responders, 95% CI: 4.17–15.44) and 7.54 mo (6 responders, 95% CI: 2.56–14.26), and median PFS was 4.07 (95% CI: 2.86–4.83) and 4.17 (95% CI: 1.45–6.87) mo. Investigator assessment was in line with BIRC assessment (Table). The most common adverse events across all cohorts (≥25%, all grades, N = 364) were peripheral edema (51.1%), nausea (44.8%) and vomiting (28.0%). Data for biomarker analysis and pts with brain metastasis will be presented at the ASCO 2020 meeting. Conclusion: Capmatinib has demonstrated activity in the subset of pts with high-level MET-amplified (GCN≥10) NSCLC, with a higher response rate in tx-naïve pts. Safety profile remains favorable and similar to previous reports of capmatinib. Clinical trial information: NCT02414139 . [Table: see text]
Poziotinib shows activity and durability of responses in subgroups of previously treated EGFR exon 20 NSCLC patients.
Authors: Le Xiuning , Goldman Jonathan Wade , Clarke Jeffrey Melson , Tchekmedyian Nishan , Piotrowska Zofia , Chu David , Bhat Gajanan , Lebel Francois M. , Socinski Mark A.
Published: May 2020

9514

Background: Treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 mutations is an unmet medical need. Poziotinib is a potent tyrosine kinase inhibitor (TKI) of EGFR and HER2 exon 20 insertion mutants. We evaluated the efficacy and safety of poziotinib in previously treated NSCLC patients with EGFR exon 20 insertion mutations in an independent cohort of a multi-cohort, multi-center Phase 2 study ( ZENITH20-1). Methods: ZENITH20-1 study enrolled pts with advanced NSCLC with an EGFR exon 20 insertion identified on local tissue testing who had received at least one prior line of therapy. Poziotinib (16 mg) was administered orally QD, allowing dose reductions for AEs, with follow up for 24 months. The primary endpoint was objective response rate (ORR), evaluated centrally by RECIST v1.1. Secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and safety. Efficacy was also evaluated by specific exon 20 insertions and prior lines of therapy. Results: 115 patients with a median age of 61 years (33-83) were enrolled. Patients had a median of 2 prior lines of therapy (range, 1-9.) The median relative dose intensity was 72% (7-100%) with 65% having dose reductions. The ORR in the as-treated population was 14.8% (95% CI 8.9 - 22.6%), and the DCR was 68.7% (95% CI 59.4 - 77.0%) with a median DoR of 7.4 months. 65% patients had tumor size reductions and the median PFS was 4.2 months. In the evaluable population (n = 88), the ORR was 19.3% and the unconfirmed ORR was 25%. Responses were predominantly observed in insertions between residues M766 to D770 of exon 20 (8/44; 18.2%). Responses were observed in patients with 2 lines (14%); ≥3 lines of therapy (16.2%). The most common treatment-related Grade ≥3 AEs were rash (28%), diarrhea (26%), stomatitis (9%) and paronychia (6%). The incidence of treatment-related pneumonitis was 4%, however some cases may have been confounded by prior checkpoint inhibitors as first line treatment. Conclusions: Although the ORR primary endpoint was not met, poziotinib induced tumor reduction in the majority of patients with durable responses, including the heavily pre-treated population. Responses were more common in patients with insertions between M766 to D770 of EGFR exon 20. The safety profile was overall consistent with other 2nd generation EGFR TKIs. Evaluation of these subgroups with refined dosing and improved toxicity management to maintain continuous treatment is warranted to assess the potential of poziotinib in Exon20 related tumors. Clinical trial information: NCT03318939 .