bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase Ib/II open-label, randomized evaluation of 2L atezolizumab (atezo) + PEGPH20 versus control in MORPHEUS-pancreatic ductal adenocarcinoma (M-PDAC) and MORPHEUS-gastric cancer (M-GC).
Authors: Ko Andrew H. , Lee Jeeyun , ALSINA MARIA , Ajani Jaffer A. , Bang Yung-Jue , Chung Hyun Cheol , Lacy Jill , Lopez Charles D. , Oh Do-Youn , O'Reilly Eileen Mary , Siveke Jens T , Allen Simon , Al-Sakaff Nedal Jaffer Abdulla , Barak Hila , Lau Janet , Li Shi , Retiere Anne-Cecile , Shemesh Colby , Zhang Xiaosong , Kim Kyu-Pyo 
Published: May 2020

4540 Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to identify early efficacy signals and safety of treatment (tx) combinations across cancers. Within MORPHEUS, atezo (anti–PD-L1) was tested with PEGylated recombinant human hyaluronidase (PEGPH20), an anti–stromal and extracellular matrix modulator, in patients (pts) with metastatic (m) PDAC or advanced/mGC. Methods: In 2 separate randomized trials, eligible pts with 2L mPDAC or mGC received atezo (1200 mg IV q3w) + PEGPH20 (3 µg/kg IV on D1, 8, 15). Control tx for M-PDAC (NCT03193190) was mFOLFOX6 or gemcitabine + nab-paclitaxel. In M-GC (NCT03281369), control tx was ramucirumab + paclitaxel. Primary endpoints were ORR (investigator-assessed RECIST 1.1) and safety. Results: Pts were followed up for ≥ 18 wk in M-PDAC (data cutoff: Aug 5, 2019) and ≥ 24 wk in M-GC (data cutoff, Jul 11, 2019). In M-PDAC, 66 pts received atezo + PEGPH20 and 42 received control in both preliminary and expansion phases. Confirmed ORRs were 6.1% (95% CI: 1.7, 14.8) and 2.4% (95% CI: 0.06, 12.6), respectively. Duration of response ranged from 5.3 to 11.3 mo in tx arm and was 3.9 mo in control. Median PFS was 1.5 mo (95% CI: 1.4, 2.6) and 2.3 mo (95% CI: 1.6, 4.0), respectively. Median OS was 7.1 mo (95% CI: 4.6, 9.5) and 6.8 mo (95% CI: 5.6, 8.3). Updated survival data will be presented. Respectively, 62.2% and 59.5% of pts had Gr 3-4 AEs; Gr 5 AEs were seen in 4.5% and 2.4% of pts; serious AEs (SAEs) occurred in 45.5% and 45.2% of pts; 16.7% and 4.8% of pts had tx-related AEs leading to tx withdrawal. The most common tx-related AEs were myalgia (65.2%) and peripheral edema (28.8%) in the combination arm. In M-GC, 13 pts received atezo + PEGPH20 and 12 received control. Confirmed ORRs were 0% (95% CI: 0, 24.7) and 16.7% (95% CI: 2.1, 48.4), respectively. Gr 3-4 AEs were seen in 30.8% and 75.0% of pts, respectively. No Gr 5 AEs occurred in either arm. SAEs occurred in 7.7% and 50.0% of pts, respectively. Only 1 pt in the control arm had a tx-related AE leading to tx withdrawal. While tumor hyaluronan (HA) appears to be associated with poor prognosis in the M-PDAC control, there was no clear association between HA levels and response to atezo + PEGPH20. PK data will also be presented. Conclusions: Limited efficacy was seen with the chemotherapy-free combination of atezo + PEGPH20 in PDAC. No efficacy was seen in GC. The safety of atezo + PEGPH20 was consistent with each agent’s known safety profile; no new safety signals were identified. Clinical trial information: NCT03193190 .
Final analysis of single-arm confirmatory study of definitive chemoradiotherapy including salvage treatment in patients with clinical stage II/III esophageal carcinoma: JCOG0909.
Authors: Ito Yoshinori , TAKEUCHI HIROYA , Ogawa Gakuto , Kato Ken , Onozawa Masakatsu , Minashi Keiko , Yano Tomonori , Nakamura Kenichi , Tsushima Takahiro , Hara Hiroki , Okuno Tatsuya , Hironaka Shuichi , Nozaki Isao , Ura Takashi , Chin Keisho , Kojima Takashi , Seki Shiko , Sakanaka Katsuyuki , Fukuda Haruhiko , Kitagawa Yuko 
Published: May 2020

4545 Background: Definitive chemoradiotherapy (dCRT) consisting of 5-fluorouracil (5-FU) and cisplatin (CDDP) with 60 Gy radiotherapy (RT) for clinical (c) Stage II/III esophageal carcinoma (EC) is a standard treatment for patients (pts) refusing surgery (S) in Japan based on the previous trial (JCOG9906). However, poor survival, high incidence of late toxicities, and severe complications of salvage S are problems. We conducted a single-arm confirmatory study of CRT modifications including salvage treatment (ST) to reduce CRT toxicities and facilitate ST to improve survival. We reported the 3-year survival at 2018 ASCO Annual Meeting. We report the final data after 5-year follow-up. Methods: EC pts with cStage II/III (UICC 6th, non-T4), PS 0-1, and age 20-75 years were eligible. Chemotherapy (CT) was CDDP (75 mg/m2 on days 1, 29) and 5-FU (1000 mg/m2/d on days 1-4, 29-32). RT was administered to a total dose of 50.4 Gy with elective nodal irradiation of 41.4 Gy. Good responders after dCRT received additional 1-2 cycles of CT. For residual or recurrent disease, salvage endoscopic resection (ER) or S was performed based on the prespecified criteria. Planned sample size was 95, with one-sided alpha of 5% and power of 80%, expected and threshold 3-year overall survival (OS) as 55% and 42%. Key secondary endpoint was ST related toxicity. Final analysis was planned after 5-year follow-up for all pts. Results: From 4/2010 to 8/2014, 96 pts were enrolled, two were ineligible and 94 were included in efficacy analysis (cStage IIA/IIB/III, 22/38/34). Complete response was achieved in 55 pts (59%). Salvage ER and S were performed in 5 (5%) and 27 pts (29%). R0 resection of salvage S was achieved in 23 (85%). With a median follow-up of 5.95 years, 3- and 5-year OS was 74.2% (90% CI 65.9-80.8%) and 64.5% (95% CI 53.9-73.3%). 5-year progression-free survival and esophagectomy-free survival were 48.3% (95% CI 37.9-58.0%) and 54.9% (95% CI 44.3-64.4%). 5-year OS after salvage S was 31.0% and hazard ratio of R1-2 to R0 was 5.635 (95% CI: 1.818-17.467). No complications occurred after salvage ER. Five pts (19%) showed ≥ grade 3 operative complications and 1 treatment related death due to bronchus-pulmonary artery fistula occurred after salvage S. Only 9 pts (9.6%) showed grade 3 late toxicities. And no late operative complications more than grade 3 were observed. Conclusions: This combined modality treatment of dCRT with ST showed acceptable toxicities, favorable 5-year survival, and promising esophageal preservation. Clinical trial information: jRCTs031180110 .
Evaluation of spatiotemporal heterogeneity of tumor mutational burden (TMB) in gastroesophageal adenocarcinoma (GEA) at baseline diagnosis and after chemotherapy.
Authors: Zhou Katherine I. , Peterson Bryan , Serritella Anthony , Reizine Natalie , Wang Yan , Catenacci Daniel V.T. 
Published: May 2020

4546 Background: Tumor mutational burden (TMB) may be a predictive marker for response to anti-PD1/PDL1 agents (IO). Molecular heterogeneity of various biomarkers for GEA has been established. To characterize heterogeneity of TMB and its clinical relevance, we compared TMB in primary (10) & metastatic (met) tumors at baseline newly diagnosed stage IV advanced GEA (aGEA), and before & after chemotherapy treatment (tx) for stage II–IV GEA. We assessed the prognostic relevance of TMB in aGEA. Methods: We retrospectively reviewed a cohort of 127 patients (pts) diagnosed with GEA in 2012–2019, for a total of 280 tumor samples with TMB data. TMB level was defined as low (≤5/Mb), intermediate (int) ( > 5/Mb, ≤15/Mb), or high (hi) (≥15/Mb), determined by Foundation One. Analysis was performed by Fisher’s exact test for PDL1/TMB, McNemar’s test for paired TMB, and univariate Cox proportional-hazards model for overall survival (OS). Results: Of 280 tumors, 50% (140/280) had low TMB, 45% (125/280) int TMB, & 5% (15/280) hi TMB. TMB ranged 0–58.6/Mb (median 5.3/Mb). Of tumors with hi TMB, 53% (8/15) were MSI-Hi, while of MSI-Hi tumors, 100% (8/8) were TMB hi. TMB level did not correlate with PDL1 status ( p= 0.83). Concordance between TMB levels of paired baseline 10 and baseline met tumors was 66% (29/44) (Table). TMB level was lower in the met than in the 10 in 23% (10/44) of cases, and higher in the met in 11% (5/44). Of 4 TMB hi baseline 10 tumors, 2 were not TMB hi in the met; of 40 TMB low/int baseline 10 tumors, 0 were TMB hi in the met ( p= 0.16). Post-tx tumors exhibited 71% (42/59) concordance of TMB levels compared to pre-tx 10 tumors. Of 2 TMB hi baseline tumors, 1 was not TMB hi in the post-tx tumor; of 57 TMB low/int baseline tumors, 0 were TMB hi in the post-tx tumor ( p= 0.32). In pts with aGEA at diagnosis, OS did not significantly differ depending on baseline 10 tumor TMB level (median OS of 21.4 [95% CI 15.4–27.9] months for TMB low, 14.6 [10.9–23.5] months for TMB int, and 9.6 [3.9–NA] for TMB hi; p= 0.3), nor depending on baseline met TMB level. Conclusions: Notable baseline spatial discordance of TMB was observed, particularly TMB hi 10 to low/int met. Discordance was also observed before & after tx, without significant increase towards TMB hi temporally. Spatiotemporal heterogeneity may impact the role of TMB as a predictive biomarker & warrants further study. [Table: see text]
Intestinal and tumor microbiome analysis combined with metabolomics of the anti-PD-L1 phase II PERFECT trial for resectable esophageal adenocarcinoma.
Authors: de Clercq Nicolien C. , van den Ende Tom , Prodan Andrei , van Berge Henegouwen Mark I. , Gisbertz Suzanne S. , Meijer Sybren L. , Schokker Sandor , Bergman Jacques J.G.H.M. , Haj Mohammad Nadia , Ruurda Jelle P. , van Hillegersberg Richard , Mook Stella , van Grieken Nicole C.T. , de Gruijl Tanja D. , Davids Mark , Bijlsma Maarten F. , Hulshof Maarten C.C.M. , Van Laarhoven Hanneke W.M. , Nieuwdorp Max 
Published: May 2020

4556 Background: Both human and rodent studies provide evidence for a role of the microbiome in patients who respond to checkpoint inhibition (CI). So far, no study has unraveled the physiological link between intestinal and tumor microbiome composition in relation to response to CI. The PERFECT trial was a single-arm phase II feasibility study investigating the addition of atezolizumab (PD-L1 inhibitor) to neoadjuvant chemoradiotherapy (nCRT) for resectable esophageal adenocarcinoma (NCT03087864). An exploratory objective of this trial was to evaluate intestinal and tumor microbiome composition including plasma metabolomics as potential biomarkers for immunological and pathological response. Methods: Using 16S rRNA gene sequencing, we analyzed fecal, duodenal and tumor samples at baseline (V0), 3 weeks after start of atezolizumab (V1), and 1 week before surgery (V2). We compared microbiome composition and metabolomics from patients with pathological complete response (pCR; ypT0N0) to patients with a pathological incomplete response. Differences in alpha diversity metrics were tested using mixed linear models. Beta-diversity associations were assessed using permutational MANOVA (adonis) and multilevel PCA (mixOmics). Biomarkers were identified using a machine learning model (XGboost) feature selection. Plasma metabolomics (Metabolon) were determined with liquid chromatography mass spectrometry (LC-MS). Results: Microbiome profiles were significantly altered after start of treatment in all sample types. None of the sample types showed a relation between alpha or beta diversity and pCR. On taxonomical level, we found that the tumor and duodenal baseline samples were weak predictors for response (AUC 0.60 and 0.62, respectively), but better compared to fecal microbiome composition (AUC = 0.49). We identified the top 20 microbes that predicted pCR best in tumor and fecal samples and found significant correlations with metabolites involved in bile acid metabolism. Conclusions: Both tumor and duodenal baseline biopsies were better predictors of pathological response compared to fecal microbiome. Microbes predictive of pCR showed significant correlations with metabolites involved in bile acid metabolism, which is known to indirectly influence immunosurveillance in cancer. Data on immune response in relation to the microbiome and metabolomics are expected Spring 2020. Clinical trial information: NCT03087864 .
Personalized antibodies for gastroesophageal adenocarcinoma (PANGEA): Secondary and final primary efficacy analyses.
Authors: Catenacci Daniel V.T. , Peterson Bryan , Chase Leah , Lomnicki Samantha , Serritella Anthony , Reizine Natalie , Liao Chih-Yi , Alpert Lindsay , Setia Namrata , Hart John , Siddiqui Uzma , Narula Sunil , Rampurwala Murtuza M. , Ji Yuan , Karrison Theodore , Polite Blase N. , Kindler Hedy L. 
Published: May 2020

4561 Background: Targeted therapies (tx) have had limited benefit in advanced (aGEA) due to baseline spatial (primary vs metastatic tumor PT/MT) & temporal molecular heterogeneity (BMH/TMH). We previously reported PANGEA methods & results: 35% BMH rate & 10 OS results achieving 1yr OS of 66% & mOS of 16.4 months (m) using the personalized tx strategy (Catenacci et al. GI ASCO 2020 Abstr356). Here we will report the TMH rates at progressive disease points (PD1 & PD2), ORR/PFS/DCR in each of 3 tx lines, time to strategy failure (TTF), & updated OS/safety. Methods: PANGEA enrolled newly diagnosed aGEA pts who then received up to 3 cytotoxic (cx) tx lines (L). Baseline tissue biomarker profiling (BP) was mandated on PT/MT & PD1/PD2, & ctDNA analysis throughout. After initiating 1L cx & upon learning MT BP results, antibody (AN) was added by a predefined prioritized tx algorithm incorporating tissue & blood BP (Table). At PD1, pts went to 2L cx + initial AN. Upon results of PD1 BP, pts changed AN only if BP evolved per tx algorithm. The same was done at PD2. The 10 endpoint was 1yr OS; enrolling 68 pts provided 80% power to detect a 63% 1yr OS compared to historical 50% 1yr OS (HR 0.67), using a 1-sided test (0.10 alpha). Results: 80 pts were enrolled, & 68 tx’d per protocol. At data cut-off 2/1/20, 15 pts were still on trial with only 2 of these pts on tx <12m (8 pts in 1L, 5 in 2L, 2 in 3L). All 68 pts had at least 1 dose of 1L tx, 87% 2L tx, & 36% 3L tx. AN assigned by the tx algorithm at 1L, OS, TTF, & ORR1/PFS1/DCR1 of 1L tx are shown in Table; 2L & 3L ORR/DCR outcomes will be shown. The 3yr & 4yr OS rates were 12% & 8%. TMH leading to molecular subgroup change by tx algorithm was 51% after 1L & 36% after 2L; details & results by subgroup will be provided. Any grade >3 non-heme tox thru all 3 tx lines was seen in 25% of pts. Conclusions: PANGEA showed superior 10 & 20 endpoint efficacy, even when excluding HER2- pts, compared to historical outcomes. Clinical trial information: NCT02213289 . [Table: see text]
Combination immunotherapy with ipilimumab and nivolumab in patients with advanced biliary tract cancers.
Authors: Klein Oliver , Kee Damien , Nagrial Adnan , Markman Ben , Underhill Craig , Michael Michael , Lum Caroline , Behren Andreas , Palmer Jodie , Tebbutt Niall C. , Carlino Matteo S. , Cebon Jonathan S. 
Published: May 2020

4588 Background: Patients (pts) with advanced biliary tract cancers (BTC) have a poor prognosis with first and second line chemotherapy resulting in modest survival benefits. Immunotherapy using single agent anti-PD-1 therapy has also shown low activity with an objective response rate (ORR) of less than 10%. Combined CTLA-4/PD-1 blockade using ipilimumab (ipi) and nivolumab (nivo) has demonstrated superior efficacy compared to single agent anti-PD-1 therapy in pts with advanced melanoma and renal cell carcinoma. To date, no trials in BTC pts with ipi/nivo therapy have been reported. Methods: 39 pts with metastatic BTCs were enrolled into the CA 209-538 clinical trial for rare cancers. Patients received nivo 3mg/kg and ipi 1mg/kg q 3 weekly for 4 doses, followed by nivo 3mg/kg q 2 weekly. Treatment continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR = CR +PR + SD). Exploratory endpoints include correlation of efficacy with biomarkers including PD-L1 expression and tumour mutation burden. Results: 39 pts with BTC were enrolled and 33 pts (85%) had received at least one prior line of systemic treatment (0-2 lines). The ORR was 24% and the CBR 45% with the median duration of response not been reached (range 2-26+months). Responses were observed in 3/14 intrahepatic, 1/10 extrahepatic, 0/2 unspecified cholangiocarcinoma and 5/13 gallbladder ca pts. None of the responding pts had a microsatellite instable tumour. 2 pts with durable partial responses were subsequently rendered surgically free of disease. Median OS and PFS were 6.1 and 3.1 months respectively. 22 (56%) pts experienced an immune –related adverse event (irAE) with grade3/4 irAEs being observed in 8 (20%) pts. Conclusions: Combination immunotherapy with ipi/nivo demonstrates significant clinical activity in a subset of patients with advanced microsatellite stable BTC. The response rate compares favourably to clinical trials investigating single agent anti-PD-1 therapy. Clinical trial information: NCT02923934 .
Comparison of response using mRECIST versus RECIST 1.1 Criteria in advanced hepatocellular carcinoma: A retrospective analysis of multicenter clinical trials.
Authors: Narang Jayant , Bajpai Surabhi , Jarecha Rudresh , Sharma Manish , Bohnsack Oliver 
Published: May 2020

4595 Background: mRECIST 2010 criteria for Hepatocellular Carcinoma (HCC) response assessment were focused on a concept of measuring viable tumor tissue showing enhancement in arterial phase of contrast enhanced CT/MRI, whereas RECIST 1.1 focuses mainly on the morphological measurements quantifying the tumor size irrespective of viability of the tumor and associated response to therapy. RECIST 1.1 does not address measures of antitumor activity other than tumor shrinkage, underestimating responses in HCC. Methods: We retrospectively analyzed multiple, phase III, multi-center clinical trials using both mRECIST and RECIST 1.1 criteria, read separately. The intent was to compare the overall responses at post-baseline assessments read independently by the two criteria. A total of 1682 subjects with 6159 post-baseline imaging timepoints were included in the analysis. The Overall response rate (ORR) as measured by sum of complete response (CR) and partial response(PR) and the Complete response rate (CRR) were evaluated. In addition, we also assessed the number of not evaluable (NE) time points by each criteria separately. We tested the following hypotheses 1. mRECIST may have better ORR and CRR compared to RECIST 1.1. 2. RECIST 1.1 may have more timepoints with Stable disease (SD) compared to mRECIST. 3. mRECIST may have more Not evaluable (NE) timepoints due to stringent imaging specifications. Results: The results are tabulated in the table below: Conclusions: The results above suggest that mRECIST shows more than double the CRR than RECIST 1.1, and the ORR is 62% higher using mRECIST than RECIST 1.1. Stable disease as expected was more commonly observed in RECIST 1.1 analysis. A NE response was 60% more common in mRECIST criteria evaluation. Our analysis confirms that reduction in viable tumor/enhancing area using contrast-enhanced radiologic imaging is the more optimal method to assess treatment response in HCC, and using RECIST 1.1 tumor measurement of a longest diameter as the sole measure of response, may not be adequate in response assessment for HCC. Our analysis validates and supports more widespread adoption of mRECIST in HCC tumor response assessment. Our results also indicate the need for uniform image acquisition and rigorous image quality control for a valid response in mRECIST criteria. [Table: see text]
A randomized phase II study of oxaliplatin/5-FU (mFOLFOX) versus irinotecan/5-FU (mFOLFIRI) chemotherapy in locally advanced or metastatic biliary tract cancer refractory to first-line gemcitabine/cisplatin chemotherapy.
Authors: Kim Jin Won , Suh Koung Jin , Kim Ji-Won , Park Jin Hyun , Kim Ki Hwan , Kim Yu Jung , Kim Jin-Soo , Kim Jee Hyun , Choi In Sil 
Published: May 2020

4603 Background: In locally advanced or metastatic biliary tract cancer (BTC), second-line chemotherapy is challenging after progression from first-line gemcitabine/cisplatin, although mFOLFOX has been proven to be superior to active symptom control in ABC-06 trial. Irinotecan is an active drug in other gastrointestinal cancers. This study evaluated whether mFOLFIRI was superior to mFOLFOX in second-line treatment of BTC. Methods: Patients diagnosed with BTC with disease progression after prior gemcitabine/cisplatin were randomized (1:1) to either mFOLFOX (oxaliplatin 100mg/m2 over 2 hours, leucovorin 100mg/m2 over 2 hours, 5-fluorouracil 2400mg/m2 over 46 hours, every 2 weeks) or mFOLFIRI (irinotecan 150mg/m2 over 2 hours, leucovorin 100mg/m2 over 2 hours, 5-fluorouracil 2400mg/m2 over 46 hours). Randomization was stratified by tumor location (intrahepatic vs extrahepatic vs gallbladder vs ampulla of vater) and ECOG performance status (0, 1 vs 2). Primary end-point was overall survival (OS) rate at 6 months. Results: In total, 120 patients were enrolled and 114 patients were treated (mFOLFOX:57, mFOLFIRI:57). Median age was 63 years old. Most patients had ECOG 0/1 (89.5%). Tumor location was intrahepatic in 47 patients (41.2%), extrahepatic in 27 (23.7%), gallbladder in 35 (30.7%) and ampulla of vater in 5 (4.4%). At the median follow-up duration of 10.7 months (95% CI, 8.2-13.2), 6-month OS rate was 58.1% in mFOLFOX and 46.0% in mFOLFIRI. Of 102 evaluable patients (mFOLFOX:51, mFOFIRI:51), objective response rate and disease control rate were 5.9% (95% CI, 0-12.4) and 64.7% (95% CI, 51.6-77.8) in mFOLFOX and 3.9% (95% CI, 0-9.2) and 58.8% (95% CI, 45.3-72.3) in mFOLFIRI. Median progression-free survival was 2.8 months (95% CI, 2.3-3.3) in mFOLFOX and 2.1 months (95% CI, 1.3-2.9) in mFOLFIRI (p = 0.682). Median OS was 6.6 months (95% CI, 5.6-7.6) in mFOLFOX and 5.9 months (95% CI, 4.3-7.5) in mFOLFIRI (p = 0.887). The most common grade 3/4 adverse events were neutropenia (26.3%) and AST/ALT elevation (15.8%) in mFOLFOX and neutropenia (24.6%) and anemia (17.5%) in mFOLFIRI. Peripheral neuropathy (36.8%) and thrombocytopenia (35.1%) in mFOLFOX and vomiting (19.3%) and cholangitis (10.5%) in mFOLFIRI occurred more frequently. No chemotherapy-related deaths were reported. Conclusions: In second-line treatment of BTC, mFOLFIRI was tolerable But, mFOLFIRI was not superior to mFOLFOX. Adverse events were different between two groups. Clinical trial information: NCT03464968 .