bluuebunny/crossref_metadata_2025_split huggingface dataset:
Is checkpoint inhibitor pneumonitis underreported in patients with advanced non-small cell lung cancer (NSCLC) on PD-1 inhibitor monotherapy?
Authors: Spieler Benjamin Oren , Lopes Gilberto , Dal Pra Alan , Diwanji Tejan , Yechieli Raphael , Freedman Laura M. , Mihaylov Ivaylo 
Published: May 2020

9579 Background: For patients with advanced non-small cell lung cancer (NSCLC), immunotherapy (ImT) has led to improvements in survival and quality of life. Checkpoint inhibitor pneumonitis (CIP) is an uncommon but sometimes life-threatening adverse event. While CIP is a diagnosis of exclusion, many oncologists believe the incidence of CIP is underreported. Radiomics, an image analysis technique that can extract imperceptible information from radiographic images, has been incorporated into predictive models for many cancers. Recent studies suggest that radiomic analysis of pre-ImT imaging can predict CIP. We hypothesized that for patients with advanced NSCLC treated with Nivolumab monotherapy, the rate of CIP is underreported and radiomics features can identify CIP that was clinically misclassified. Methods: From an IRB-approved database (DB) of 159 patients with advanced NSCLC treated with Nivolumab, chart review identified 8 patients diagnosed with CIP of any grade (5%). 42 additional patients from the same DB without diagnosis of CIP were randomly selected for analysis. For all 50 patients, uninvolved lung in the last pre-ImT CT imaging study was segmented, delineated, and analyzed for radiomics features associated with CIP. A logistic regression model incorporating radiomics assigned a CIP probability score to every patient. Results: Six radiomics features correlated with CIP ( p-values range from 0.02 to 0.03). Each feature had an AUC of ~0.79 (range 0.789 to 0.794) showing large effect size, with odds ratios greater than 3.50 (4 features) or less than 0.3 (2 features). The radiomics-based probability model assigned 7/42 patients (17.5%) without clinical diagnosis of CIP a greater than 50% probability of CIP. Chart review revealed that 6/7 “misclassified” patients exhibited symptoms or radiographic features highly suggestive of CIP within 5 months of initial immunotherapy treatment. These indications originally had been attributed to disease progression, overshadowed by more severe symptoms or simply mislabeled (e.g. a case of recall pneumonitis was described as "radiation pneumonitis"). Conclusions: For patients with advanced NSCLC treated with nivolumab, the incidence of checkpoint-inhibitor pneumonitis (CIP) is underreported and radiomics features can help identify CIP that has been clinically misclassified. Future directions include expansion of this study across the full database, correlation of radiomics features with blood biomarkers, and the inclusion of tumor burden as an additional covariate in the analysis.
Large scale clinico-genomic analyses among patients with BRAF-mutated non-small cell lung cancers (NSCLC) identified by nationwide genomic screening project (LC-SCRUM-Japan).
Authors: Sakai Tetsuya , Matsumoto Shingo , Nakagawa Taku , Ohashi Kadoaki , Itani Hidetoshi , Shingyoji Masato , Nakamura Atsushi , Toyozawa Ryo , Mori Masahide , Tuda Takeshi , Ohe Yuichiro , Sakamoto Tomohiro , Kato Terufumi , Ikeda Takaya , Zenke Yoshitaka , Udagawa Hibiki , Kirita Keisuke , Yoh Kiyotaka , Niho Seiji , Goto Koichi 
Published: May 2020

9590 Background: BRAF mutations are functionally classified into three groups, comprisingV600-mutant kinase-activating monomers (class I), kinase-activating dimers (class II), kinase-inactivating heterodimers (class III). The difference of clinical outcomes and concomitant genetic alterations among the three classes in non-small cell lung cancers (NSCLC) are unclear. Methods: We have prospectively analyzed NSCLC patients (pts) for cancer-related genes by a next-generation sequencing system, Oncomine™ Comprehensive Assay, in a large-scale genome screening project in Japan (LC-SCRUM-Japan). The clinical characteristics and outcomes of pts with BRAF-mutated non-squamous (non-sq) NSCLC were comparatively evaluated among the three classes of BRAF mutations. Results: A total of 5166 non-sq NSCLC pts were enrolled into the LC-SCRUM-Japan from 2015 to 2019. BRAF mutations were detected in 176 pts (3%). Among the 176 pts, 153 (87%) were classified into the three classes according to the mutation variants, including 65 (42%) into class I, 52 (34%) into class II and 36 (24%) into class III. The remaining 23 were not classified into any of the three classes. Compared with class I, class II or class III was significantly associated with smoking (P = 0.02 and < 0.01, respectively). Concomitant RAS mutations were significantly more frequent in class II and class III than in class I (P < 0.01 and = 0.04, respectively). The frequency of concomitant STK11 mutations was significantly higher in class III than in others (P < 0.01, respectively). There was no significant difference in the frequency of other oncogene and tumor suppressor gene mutations among the three classes. In the 1st-line platinum-containing chemotherapies for advanced or recurrent cases, median progression-free survival (mPFS) of class III pts was shorter than class I or class II pts (4.2, 11.5 and 4.8 months, I vs III; P < 0.01, II vs III; P = 0.06). In the treatment with 2nd-4th line PD-1/PD-L1 inhibitors, mPFS was not significantly different among the three classes. Overall survival of class III pts was significantly shorter than class I pts (11.9 vs 35.2 months, P = 0.03). Conclusions: Concomitant gene mutations and clinical features are largely different among the BRAF mutation classes. Especially in class III, concomitant RAS and STK11 mutations are more frequent and clinical outcomes were significantly less favorable. These results suggest the need of novel therapeutic strategy based on the mutation class for BRAF-mutated lung cancers.
Genomic testing among patients (pts) with newly diagnosed advanced non-small cell lung cancer (aNSCLC) in the United States: A contemporary clinical practice patterns study.
Authors: Gondos Adam , Paz-Ares Luis G. , Saldana Diego , Thomas Marlene , Mascaux Céline , Bubendorf Lukas , Barlesi Fabrice 
Published: May 2020

9592 Background: We describe contemporary clinical patterns of guideline-mandated genomic testing in newly diagnosed US pts with aNSCLC. Methods: From the Flatiron Health electronic health record-derived de-identified database, we included pts with newly diagnosed advanced non-squamous cell carcinoma of the lung between 1.1.2018–6.30.2019 who had received first-line (1L) therapy. We defined inadequate testing as no successful test for at least one of four examined genes: ALK, BRAF, EGFR, and ROS1. We grouped pts according to testing received into users of next-generation sequencing (NGS) testing, including a subgroup using comprehensive genomic profiling (CGP, exemplified by Foundation Medicine, Inc.), users of non-NGS testing, and no testing. We describe the following aspects of genomic testing before the start of 1L therapy: occurrence of testing, patterns of use of testing technologies, occurrence of inadequate testing, test failures, percentage of pts with potentially missed targeted therapy with US Food and Drug Administration approval (no positive test and <4 successful tests), and recent trends in genomic testing. Results: Among 2971 included pts, 690 (23.2%) had no genomic testing before 1L treatment. Among pts who had a test (n=2281), 59.4% (n=1355) received NGS (CGP: 18.8%, n=429), while 40.6% (n=926) received non-NGS tests only. In the CGP user group, 79.7% of pts received no other type of test, compared with 29.8% of pts in the other NGS group. Inadequate testing was recorded in 13.4% of NGS-tested pts (CGP: 4.9%), compared with 52.5% of pts tested by non-NGS only. Test failures contributed to unsuccessful testing in 4.2% of pts tested by NGS (CGP: 1.2%) and in 6.8% of pts who received non-NGS tests. In the NGS group, 10.1% (CGP: 3.0%) of patients potentially missed a targeted therapy option, compared with 40.3% in the non-NGS group. EGFR and ALK testing were performed in ≥95% of pts, regardless of the testing group; however, only 83.6% and 55.7% of pts received tests for ROS1 and BRAF, respectively, in the non-NGS group. In the latter group, for the first 6 months of 2019, 88.4% and 58.2% of pts were tested for ROS1 and BRAF mutations, respectively. Conclusions: Not performing any, or performing only inadequate genomic testing in pts with newly diagnosed aNSCLC remains a concern in clinical practice. The use of NGS, particularly CGP, may help to avoid suboptimal testing, minimize test failures, and improve uptake of testing for newly introduced biomarkers, enabling individualized, targeted therapy.
Blood serum amyloid A as potential biomarker of pembrolizumab efficacy for patients affected by advanced non-small cell lung cancer (NSCLC) overexpressing PD-L1: Early results of the FoRECATT Study.
Authors: Di Noia Vincenzo , D'Argento Ettore , Pilotto Sara , Carbone Carmine , Vita Emanuele , Ceresoli Giovanni Luca , Beretta Giordano D. , Tortora Giampaolo , Bria Emilio 
Published: May 2020

9598 Background: Identifying the patients who may benefit the most from immune checkpoints inhibitors remains a great challenge for clinicians. The tumor-derived Serum Amyloid A (SAA) inhibits the immune-response in melanoma patients. Here we present the early results of FoRECATT study investigating on blood SAA as biomarker of response to upfront pembrolizumab in patients with advanced non-small-cell lung cancer (NSCLC). Methods: In this prospective study, patients with PD-L1 ≥ 50% receiving upfront pembrolizumab (P cohort) and with PD-L1 0-49% treated with chemotherapy (CT cohort), were evaluated for blood SAA and radiological response at baseline and every 9 weeks. Primary endpoint was response rate (RR) according to Response Evaluation Criteria in Solid Tumors 1.1; secondary endpoints were progression-free (PFS) and overall survival (OS). The most accurate SAA cut-off to predict response was established with ROC-analysis in the P cohort. Results: In the P Cohort (n = 42), the overall RR was 38%. After a median follow-up of 18.5 months (mo), baseline SAA ≤ the ROC-derived cut-off (29.9 mg/L; n = 14/42, 33%) was significantly associated with higher RR (53.6 versus 7.1%; OR 15, 95%CI 1.72-130.7, P= 0.009), longer PFS (17.4 versus 2.1 mo; P< 0.0001) and OS (not reached versus 7.2 mo; P< 0.0001) compared with SAA > 29.9 mg/L. In multivariate analysis, low SAA positively affects PFS ( P= 0.001) and OS ( P= 0.048) irrespective of ECOG PS, number of metastatic sites and pleural effusion. SAA monitoring (n = 40) was also significantly associated with survival endpoints: median PFS 17.4 versus 2.1 mo and median OS not reached versus 7.2 mo when SAA remained low (n = 14) and high (n = 12), respectively. In the CT Cohort (n = 30), RR was not significantly affected by SAA level, while low SAA at baseline (n = 17) was associated with better PFS (HR = 0.42, 95%CI 0.16-1.10, P= 0.02) and OS (HR = 0.16, 95% CI 0.04-0.55, P= 0.0004). Conclusions: Low SAA predicts a higher likelihood of response to upfront pembrolizumab only and good survival outcomes irrespective of treatment in advanced NSCLC patients. Therefore, a simple blood test might be useful to identify patients likely to derive better outcomes from immunotherapy. A further study (FoRECATT-2) is ongoing to confirm the results in a larger validation cohort and to assess the potential effect of SAA on immune response in vitro assays.
Outcomes in patients with metastatic non-small cell lung cancer (mNSCLC) with brain metastases treated with pembrolizumab-based therapy.
Authors: Sun Lova , Davis Christiana , Marmarelis Melina Elpi , Jeffries Seth , Sulyok Lydia Frenzel , Hwang Wei-Ting , Singh Aditi Puri , Berman Abigail T. , Feigenberg Steven J. , Levin William C. , Bauml Joshua , Ciunci Christine Agnes , Cohen Roger B. , Langer Corey J. , Aggarwal Charu 
Published: May 2020

9599 Background: Patients (pts) with mNSCLC with active brain metastases (BM) are often excluded from clinical trials; data on efficacy and safety of immunotherapy in this population are limited. We compared outcomes of pts with mNSCLC with and without BM who received pembrolizumab-based therapy. Methods: We conducted a retrospective single-center study of pts with mNSCLC treated with pembrolizumab (P) with or without chemotherapy. Progression-free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier methodology and compared using multivariable Cox regression and log rank testing. Results: We identified 587 consecutive pts with mNSCLC who began P-based therapy between 8/2013 and 12/2018: 306 (52%) female, median age 67 years (range 32-98), 437 (74%) adenocarcinoma, and 508 (87%) former/current smokers. 388 (66%) patients received P in first line therapy, and 334 (57%) received single-agent P. 131 pts (22%) had detectable BM at baseline (start of P-based therapy). Pts with BM were younger (median 65 y vs 68 y, p < 0.01) and more likely to have adenocarcinoma (86% vs. 71%, p < 0.01) and baseline steroid use (22% vs 1%, p < 0.01). Presence of BM did not differ by race, sex, line of therapy, treatment regimen, or PD-L1 status. Of the 131 patients with detectable BM on pre-treatment brain MRI, 55 (42%) had stable BM as a result of prior local therapy, while 76 (58%) had active (new or growing) BM on pre-treatment imaging. Most patients with active BM underwent radiation therapy (RT) in either the 30 days before (n = 46) or 30 days after (n = 17) P start; of the remaining 13 treated with P-based therapy alone, intracranial responses included 2 CR, 2 PR, 3 SD, and 4 PD. As of 1/1/2020, with 15-month median follow up, there was no difference in mPFS (9.2 vs 7.3 months, p = 0.41) or mOS (18.3 vs 18.0 mo, p = 0.67) between pts with and without BM in our P-treated cohort. On multivariable analysis, female sex, ECOG 0-1, adenocarcinoma histology, and P as first line therapy were associated with improved PFS and OS. Presence of BM, baseline steroid use, and timing of local RT (before vs. after P) were not associated with inferior survival. Conclusions: In our single-center experience of pts with mNSCLC treated with P, pts with and without BM had similar PFS and OS. We observed several intracranial responses to P-based therapy alone, but most pts with active BM underwent local RT. mNSCLC pts with BM should be considered for P-based therapy; BM may be treated with RT immediately before or even after P with similar survival outcomes.
Physiologic colonic uptake of 18F-FDG on PET/CT predicts immunotherapy response and gut microbiome diversity in patients with advanced non-small cell lung cancer (NSCLC).
Authors: Cvetkovic Lena , Régis Claudine , Iebba Valerio , Derosa Lisa , Leblond Antoine , Malo Julie , Messaoudene Meriem , Belkaid Wiam , Elkrief Arielle , Routy Bertrand , Juneau Daniel 
Published: May 2020

9600 Background: Immune checkpoint inhibitors (ICI) represent the backbone treatment of advanced non-small cell lung cancer (aNSCLC) patients. Emerging evidence suggests increased gut microbiome (GM) diversity is associated with favorable response. Conversely, antibiotic-induced dysbiosis may be associated with deleterious outcomes in patients receiving ICI in multiple retrospective studies and one prospective study. 18F-FDG physiologic colonic uptake on PET/CT increases following treatment with antibiotics and could be a surrogate marker for GM diversity and therefore clinical response. The aim of this study was to determine if 18F-FDG physiologic colonic uptake prior to ICI initiation correlates with outcomes and GM metagenomics in patients with advanced NSCLC. Methods: 71 patients with aNSCLC who underwent PET/CT prior to ICI were identified. For each patient, the colon was manually contoured, SUVmax was measured in each segment of the colon by a nuclear medicine specialist and average SUVmax was calculated for the whole colon. Patients were stratified in two groups according to median colon SUVmax (low vs high uptake). 18F-FDG physiologic colonic uptake was then compared to overall survival (OS), objective response (ORR), and progression-free survival (PFS). For patients with available stool samples (n = 10), GM composition was defined using metagenomics sequencing. Results: 71 patients (54% men, median age: 68 years) with aNSCLC were included in the study and ICI was the first line of therapy in 38% of those patients. The mean colon SUV for the low and high uptake groups were 1.41 (CI 95% 1.35-1.47) and 2.18 (CI 95% 1.90-2.46) respectively. The high uptake group had a higher proportion of non-responders (p = 0.033) and significant shorter PFS (4.1 months vs 11.3 months, p = 0.005). In the caecum, high uptake also correlated with numerically shorter OS (10.82 vs 27.56 months, p = 0.058) compared to low uptake group. Despite the low number of samples, metagenomics sequencing revealed that PLS-DA (Partial Least Squares Discriminant Analysis) for diversity was lower in the high SUV group (p = 0.008). Conclusions: Higher colon SUVmax on pre-ICI FDG PET/CT is associated with worse clinical outcomes and lower baseline GM diversity in patients with advanced NSCLC. Here, we propose that 18F-FDG physiologic colonic uptake on PET/CT could serve as a surrogate marker of GM diversity and predicts clinical outcomes.
Dose escalation and expansion from the phase I study of DS-1062, a trophoblast cell-surface antigen 2 (TROP2) antibody drug conjugate (ADC), in patients (pts) with advanced non-small cell lung cancer (NSCLC).
Authors: Lisberg Aaron Elliott , Sands Jacob , Shimizu Toshio , Greenberg Jonathan , Phillips Penny , Guevara Ferdinand M. , Noguchi Yutaka , Toki Tadashi , Spira Alexander I. , Yamamoto Noboru , Johnson Melissa L. , Meric-Bernstam Funda , Yoh Kiyotaka , Garon Edward B. , Heist Rebecca Suk 
Published: May 2020

9619 Background: TROP2 is an intracellular calcium signaling transducer overexpressed in NSCLC, portending poor survival. DS-1062 is a TROP2-targeting ADC with a novel topoisomerase 1 inhibitor (exatecan derivative, DXd) and promising preclinical antitumor activity. Updated results inclusive of 24 additional dose escalation pts and 32 dose expansion pts from an ongoing phase 1 study of DS-1062 in advanced/metastatic NSCLC are reported (NCT03401385/J101). Methods: Pts aged ≥18 (US) or ≥20 (Japan) with unresectable NSCLC refractory to/relapsed from standard treatment with measurable disease (RECIST v1.1) and available tumor for retrospective TROP2 evaluation were eligible. Primary objectives include maximum tolerated dose (MTD) identification, safety, and tolerability and secondary objectives include efficacy, pharmacokinetics, and incidence of anti-drug antibodies against DS-1062. Pts were eligible regardless of TROP2 level. Results: As of November 16, 2019, 95 pts were treated with ≥1 dose of DS-1062. 63 pts were treated during escalation at 0.27 (n = 4), 0.5 (n = 5), 1.0 (n = 7), 2.0 (n = 6), 4.0 (n = 6), 6.0 (n = 19), 8.0 (n = 8), and 10.0 (n = 8) mg/kg and 32 pts were treated in expansion at the MTD of DS-1062, 8 mg/kg. 59 pts (62%) discontinued (25 [42%] due to progressive disease per RECIST v1.1). Pts were exposed to a median of 3 treatment cycles (range, 1-19). In 88 response-evaluable pts, 22 had partial response (1 PR/6 pts at 2.0 mg/kg, 2 PR/6 pts at 4.0 mg/kg, 5 PR/18 pts at 6.0 mg/kg, 13 PR/34 pts at 8.0 mg/kg, and 1 PR/8 pts at 10.0 mg/kg; 14 PRs were confirmed and 8 PRs are awaiting confirmation). Treatment emergent adverse events (TEAEs) regardless of causality were reported in 91 of 95 pts (96%; 44 pts [46%] experienced ≥grade 3, 30 pts [32%] had serious events). Treatment-related TEAES were reported in 76 of 95 pts (80%; 17 pts [18%] experienced ≥grade 3, 8 pts [8%]) had serious events). Potential interstitial lung disease (ILD) occurred in 8 pts (8%; 2 at 6.0 mg/kg and 6 at 8.0 mg/kg); 6/8 with potential ILDs adjudicated as treatment-related (1 at 6.0 mg/kg [grade 2] and 5 at 8.0 mg/kg [1 grade 1, 2 grade 2, 1 grade 3, and 1 grade 5]). 14 escalation pts and 22 expansion pts remain on trial. Updated trial details/results will be presented. Conclusions: In this first-in-human study of DS-1062, treatment was well tolerated up to 8 mg/kg, and a dose effect on antitumor activity was observed over 2.0-10.0 mg/kg in heavily pretreated pts with prior progression on standard treatment. Clinical trial information: NCT03401385 .
Acquired resistance to PD-1 blockade in NSCLC.
Authors: Schoenfeld Adam Jacob , Rizvi Hira , Memon Danish , Luo Jia , Preeshagul Isabel Ruth , Sauter Jennifer L. , Plodkowski Andrew J. , Vanderbilt Chad , Miller Martin L. , Hellmann Matthew David 
Published: May 2020

9621 Background: Although durability is the trademark characteristic of response to PD-1 blockade, acquired resistance can occur. The frequency, patterns, and survival outcomes of patients with acquired resistance to PD-1 blockade are unknown. Methods: All patients with NSCLC treated with PD-1 blockade at MSKCC were examined. Acquired resistance was defined as initial CR/PR (by RECIST) followed by progression/death. Oligo vs systemic patterns of acquired resistance were defined as progression in ≤ 2 sites of disease or ≥ 3 sites of disease, respectively. Results: Of 1201 patients treated with PD-1 blockade, 243 (20%) achieved initial response and 189 (78%, 95% CI 72-83%) eventually developed acquired resistance (AR). Onset of AR was variable and decreased with longer duration of response (53% within 1 year, 37% 1-2 years, 10% > 2 years). Patients with PD-L1 expression < 50% and TMB < 8mut/Mb were more likely to develop resistance compared those with PD-L1 expression ≥50% and TMB ≥8mut/Mb (OR 5.5, p = 0.02). Unlike organ sites of primary refractory disease, AR commonly occurred in lymph nodes (41%) and infrequently in the liver (6%). Patterns of AR were most commonly oligo rather than systemic (79/141 [56%], 39/141 [28%]); some patients died without radiographic progression (23/141 [16%]). Oligo-AR occurred later (median onset 13 vs 5.6 mo) and associated with improved post-progression survival (median OS 55.2 vs 9.2 mo, HR 6.0, p < 0.001) compared to systemic-AR. Post-progression survival was highest in patients with AR compared to those with initial SD or PD to PD-1 blockade (median 18.9 vs 12.5 vs 4.4, p < 0.001). Of 49 patients treated initially with locally-directed therapy for AR, 28 (57%) remain alive and systemic therapy-free. Conclusions: Acquired resistance to PD-1 blockade is common in NSCLC. Risk of acquired resistance is lower in biomarker-enriched patients and with increased duration of response. Patterns of acquired resistance is commonly oligo in nature, which is amenable to locally-directed therapy and can be associated with improved survival. Differences in organ-site distribution and post-progression survival suggest distinct biology associated with acquired resistance vs primary refractory disease.