bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic CRC, gastric cancer (GC), SCCHN, or other tumors.
Authors: Tabernero Josep , Powderly John D. , Hamid Omid , Gordon Michael S. , Fisher George A. , Braiteh Fadi S. , Garbo Lawrence E. , Fine Gregg Daniel , Kowanetz Marcin , McCall Bruce , Shen Xiaodong , Chen Daniel S. , Kohrt Holbrook Edwin 
Published: March 2020

3622 Background: PD-L1 has been reported to be expressed broadly in human cancer and can lead to inhibition of anti-tumor T-cell responses. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Pts with a broad range of tumors were examined in an expansion study with MPDL3280A. Methods: Pts with locally advanced or metastatic tumors received MPDL3280A administered IV q3w. Pts were treated for up to 1 y. Response was assessed by RECIST v1.1. Results: As of Jan 10, 2013, 20 pts with tumor types other than NSCLC, RCC and mM were evaluable for safety and treated at doses of 0.01-20 mg/kg (≤1 [n=3], 3 [n=1], 10 [n=3] and 20 mg/kg [n=13]). Median pt age was 67 y (range 26-80 y), 100% were PS 0-1, 90% had prior surgery and 45% had prior radiotherapy. 95% of pts received prior systemic therapy. Pts received MPDL3280A treatment for a median of 96 days (range 22-330). The incidence of all G3/4 AEs, regardless of attribution, was 50%. No G3-5 pneumonitis or diarrhea was reported. Confirmed RECIST responses were observed in several tumor types, including CRC, GC and SCCHN. Additionally, antitumor activity (tumor shrinkage that has not yet met criteria for a RECIST response) has been observed in sarcoma and lymphoma. Analysis of biomarker data from archival tumors revealed that all pts reported to have RECIST response had baseline tumors that were PD-L1 positive. Updated data will be presented. Conclusions: Treatment with MPDL3280A was well tolerated, with no pneumonitis-related deaths. Rapid responses were observed in pts with CRC, GC and SCCHN. PD-L1 tumor status appears to correlate with responses to MPDL3280A. These data suggest that PD-L1 is a conserved mechanism for mediating tumor immune escape across a range of tumor types. MPDL3280A may be broadly active as anti-cancer therapy in PD-L1–expressing tumors, supporting further investigation. Clinical trial information: NCT01375842.
Prognostic biomarkers in a series of stage II colon cancer.
Authors: Santos Cristina , Terricabras Marta , Lopez-Doriga Adriana , Gonzalez Sara , Fernandez Anna , Martinez Iniesta Maria , Sanjuan Xavier , Garcia-Molleva David , Villanueva Alberto , Moreno Victor , Biondo Sebastiano , Kreisler Esther , Capella Gabriel , Salazar Ramon 
Published: March 2020

3629 Background: Different clinico-pathological factors are used to define a group of patients with high-risk stage II colon cancer (CC) that may benefit of adjuvant treatment. Moreover, several molecular markers, such as microsatellite instability (MSI) and BRAF, have been widely investigated as prognostic factors. Recently a high stroma component (EMT+ subtypes) has also been associated with poor outcome. The aim of the study is to analyze the prognostic value of MSI, BRAF and tumor-stroma ratio in a prospective series of stage II CC patients. Methods: FFPE tissue from 432 stage II CC patients operated at Hospital Universitari de Bellvitge (1996 - 2006) were included in the study. MSI status was assessed by the analysis of 5 mononucleotide repeat markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27). BRAF V600E mutation was analyzed by single strand conformation polymorphism technique. Tumor-stroma ratio was analyzed by immunohistochemistry. Associations between molecular factors and clinical features were assessed by Chi-Squared (X2) tests. A Cox regression model was used to evaluate the Relapse Free (RFS) and the Colon Cancer specific Survival. Results: MSI status could be determined in 350 patients. 48 (14%) had MSI high (MSI-H) tumor. BRAF status could be assessed in 380 cases. 58 (15%) cases were BRAF mutated. Tumor-stroma ratio was analyzed in 407 tumor samples. 176 (43%) tumors had more than 50% intra-tumor stroma and were classified as stroma-high. MSI-H tumors were significantly located in right colon (X2 p-value = 1.03e-5), were poorly differentiated (X2 p-value = 0.003) and had more than 12 lymph nodes resected (X2 p-value = 0.037). MSI-H tumors were associated with BRAF mutation (X2 p-value = 0.02) and stroma-low (X2 p-value = 0.0005). When a molecular prognostic risk classification was performed, patients with MSI-H /stroma-low suggested a low risk of relapse comparing to MSI-H/stroma-high, microsatellite stable (MSS)/stroma-low and MSS/stroma-high patients (HR = 3.15; 95 CI, 0.76 – 13.1, p-value = 0.0602). Conclusions: MSI-H tumors have BRAF mutation as well as low intra-tumor stroma. Our results suggest that tumor-stroma ratio can explain differential prognosis in MSI-H stage II tumors.
Analysis of KRAS/NRAS mutations in PEAK: A randomized phase II study of FOLFOX6 plus panitumumab (pmab) or bevacizumab (bev) as first-line treatment (tx) for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC).
Authors: Schwartzberg Lee Steven , Rivera Fernando , Karthaus Meinolf , Fasola Gianpiero , Canon Jean-Luc , Yu Hua , Oliner Kelly S. , Go William Y. 
Published: March 2020

3631 Background: PEAK estimated the tx effect of FOLFOX6 with pmab or bev in 1st-line WT KRAS mCRC. The PRIME study showed significantly improved progression free survival (PFS) and overall survival (OS) with pmab + FOLFOX vs FOLFOX in pts with WT RAS (KRAS/NRAS exons 2, 3, 4) mCRC in a prospective-retrospective analysis (unpublished data). Methods: This prospective-retrospective analysis of PEAK was designed to assess the effect of pmab + FOLFOX6 or bev + FOLFOX6 on PFS (primary endpoint) and OS in WT RAS (KRAS/NRAS exons 2, 3, 4) mCRC. Pts were required to have WT KRAS exon 2 tumors. Bidirectional Sanger sequencing and Transgenomic SURVEYOR/WAVE analysis were independently conducted to detect mutations in KRAS exon 3 (codons 59/61), exon 4 (codons 117/146); NRAS exon 2 (codons 12/13), exon 3 (codons 59/61), exon 4 (codons 117/146); BRAF exon 15 (codon 600) in banked specimens. Results: 285 WT KRAS (exon 2) mCRC patients (pts) were randomized, 278 received tx. The current RAS ascertainment rate is 75%. Tx HRs (pmab:bev) for pts with WT RAS were 0.63 (95% CI, 0.43-0.94; p = 0.02) for PFS and 0.55 (95% CI, 0.30-1.01; p = 0.06) for OS (Table). The incidence of worst grade 3-5 adverse events was consistent with the primary analysis. Updated OS and BRAF results will be presented. Conclusions: In this 1st-line estimation study in WT RAS mCRC, PFS and OS HR favored pmab + FOLFOX6 relative to bev + FOLFOX6, suggesting that activating RAS mutations appear to be predictive for pmab tx effect. The safety profile for both arms was consistent with previously reported studies. Clinical trial information: NCT00819780. [Table: see text]
Regorafenib (REG) in progressive metastatic colorectal cancer (mCRC): Analysis of age subgroups in the phase III CORRECT trial.
Authors: van Cutsem Eric , Sobrero Alberto , Siena Salvatore , Falcone Alfredo , Ychou Marc , Humblet Yves , Bouche Olivier , Mineur Laurent , Barone Carlo , Adenis Antoine , Argilés Guillem , Yoshino Takayuki , Lenz Heinz-Josef , Goldberg Richard M. , Sargent Daniel J. , Cihon Frank , Wagner Andrea , Laurent Dirk , Cupit Lisa , Grothey Axel 
Published: March 2020

3636 Background: In the CORRECT phase III trial, the multikinase inhibitor REG demonstrated significant improvement in overall survival (OS) and progression-free survival vs placebo (Pla) in patients (pts) with mCRC whose disease progressed on other standard therapies. The most frequent REG-related grade ≥3 adverse events (AEs) of interest were hand–foot skin reaction (HFSR), fatigue, diarrhea, hypertension, and rash/desquamation. We explored whether the impact of REG in pts aged ≥65 years differed from that in younger patients. Methods: Pts with mCRC progressing following all other available therapies were randomized 2:1 to receive REG 160 mg once daily (n=505) or Pla (n=255) for the first 3 weeks of each 4-week cycle. The dose could be modified to manage AEs. The primary endpoint was OS. We report efficacy, safety, and dosing data from REG recipients by age. Results: The REG treatment group included 309 pts <65 years (307 evaluable for safety) and 196 pts ≥65 years (193 evaluable for safety). The OS hazard ratio (REG/Pla) was 0.72 (95% confidence interval [CI] 0.56–0.91) in pts <65 years and 0.86 (95% CI 0.61–1.19) in pts ≥65 years (interaction p-value = 0.405). Median OS was 6.7 vs 5 months for REG vs Pla in pts <65 years, and 6.0 vs 5.6 months, respectively, in pts ≥65 years. Most pts experienced drug-related AEs (<65 years: 93.8%; ≥65 years: 91.7%). The rates of grade ≥3 REG-related AEs of interest and dose modifications are shown in the Table. In pts <65 years vs ≥65 years, median (interquartile range [IQR]) duration of REG was 7.6 weeks (6.6–15.4) vs 7.1 weeks (5.1–17.2), median (IQR) daily REG dose was 160.0 mg (134.6–160.0) vs 160.0 mg (137.5–160.0), and median (IQR) proportion of planned REG dose was 83.3% (65.7–100.0) vs 78.6% (66.7–100.0), respectively. Conclusions: In the CORRECT trial, REG demonstrated an OS benefit in pts <65 years and ≥65 years. Safety and tolerability of REG appeared to be similar in both age subgroups. Clinical trial information: NCT01103323. [Table: see text]
Randomized phase III clinical study comparing postoperative UFT/LV,UFT+LV/UFT and UFT+LV+PSK/UFT+PSK as adjuvant therapy for curatively resected stage III colorectal cancer HGCSG-CAD study.
Authors: Shichinohe Toshiaki , Komatsu Yoshito , Akazawa Kohei , Yuki Satoshi , Fukushima Hiraku , Ohno Kouichi , Nakamura Fumitaka , Kusumi Takaya , Morita Takayuki , Senmaru Naoto , Kumagai Naoko , Hirano Satoshi 
Published: March 2020

3638 Background: Study showed that the oral anticancer agent UFT/LV is useful as postoperative adjuvant chemotherapy for stage III colorectal cancer. PSK, a protein-bound polysaccharide extracted from the mycelia of Coriolus versicolor, is an immunomodulator widely used in gastric, colorectal and lung cancers. Methods: Patients aged 20-80 years with stage III colorectal cancer registered in 35 facilities were randomized to: group A (UFT/LV 28 days/5 weeks for 6 months); group B (UFT+LV 28 days/5 weeks for 6 months, then UFT for 12 months); and group C (UFT+LV+PSK 28 days/5 weeks for 6 months, then UFT+PSK for 12 months). Treatment was started within 6 months after curative resection. Outcome measures were relapse-free survival (RFS), overall survival (OS), incidence and severity of adverse events, and QOL. Results: Of 342 patients registered, 340 eligible patients were analyzed (84 in group A, 85 in group B, and 171 in group C). At baseline, variation in QOL score was observed but histopathological parameters were not different among 3 groups. Median observation period was 36 months. 3-year RFS was 73.8%, 77.6% and 73.9% in groups A, B, and C [A vs C: hazard ratio (HR) 0.960, 95% confidence interval (CI) 0.575-1.601; B vs C: HR 0.837, CI 0.488-1.433; A vs B: HR 1.151, CI 0.623-2.126]. 3-year OS was 95.2%, 91.8% and 89.9% in groups A, B, and C (A vs C: HR 0.460, CI 0.155-1.367; B vs C: HR 0.814, CI 0.338-1.963 A vs B: HR 0.570, CI 0.167-1.947). Adverse events ≥grade 3 included gastrointestinal symptoms and general status. There was no treatment-related death. Excluding high fatigue score in QOL scale that showed pretreatment variation, stratification analysis showed interaction between family score and group, and efficacy was suggested especially in group C with high score (3-yesr RFS: 66.7%, 68.2% and 88.1% in groups A, B, and C. A vs C: HR 3.289, CI 0.951-11.375, B vs C: HR 3.070, CI 0.973-9.685, A vs B: HR 1.084, CI 0.344-3.417). Conclusions: A significant difference in primary endpoint was not detected. Variation in QOL at treatment initiation probably greatly affected outcome. Clinical trial information: NCT00209742.
Phase II, randomized, double-blind placebo-controlled trial of nimotuzumab plus gemcitabine compared with gemcitabine alone in patients (pts) with advanced pancreatic cancer (PC).
Authors: Strumberg Dirk , Schultheis Beate , Ebert Matthias Philip , Kerkhoff A. , Hofheinz Ralf Dieter , Behringer Dirk M. , Schmidt Wolfgang E. , Goker Erdem , De Dosso Sara , Kneba Michael , Yalcin Suayib , Overkamp Friedrich , Schlegel Frank , Dommach M. , Rohrberg Robert , Steinmetz Tilman , Reuter Dirk , Bach Ferdinand 
Published: March 2020

4009 Background: FOLFIRINOX significantly increases survival in metastatic PC compared to gemcitabine, but its use is limited to selected pts, due its high toxicity. In the majority of cases, gemcitabine (gem) remains the mainstay of palliative treatment, although its modest impact on survival and disease progression. The addition of the EGFR tyrosine kinase inhibitor erlotinib prolonged median survival for only 2 weeks.This study was aimed to investigate the effect of adding Nimotuzumab (nimo), an anti-EGFR monoclonal antibody, to first-line gemcitabine, in PC. Methods: Pts with previously untreated, unresectable, locally-advanced or metastatic PC were randomly assigned to receive gem: 1000 mg/m2/ 30-min iv once weekly (d1, 8, 15; q28) and nimo: fixed dose of 400 mg once weekly as a 30-min infusion, or placebo, until progression or unacceptable toxicity. Primary endpoint was overall survival (OS) in the intention-to-treat (ITT) population. Secondary endpoints included PFS, safety, objective response rate (ORR), QoL. Results: Between 9/2007- 10/2011 a total of 192 pts were randomized (average age 63.6 ±10 years; 60% male; 69% ECOG PS 0), and 186 were evaluable at the ITT analysis. One-year OS was 19.5 % with gem+placebo and 34.4% with gem+nimo (HR=0.69; p=0.034). Median OS and PFS were 6.0 mo in the gem+placebo group, vs. 8.7 mo in gem+nimo (HR=0.83; p=0.21), and 3.7 vs. 5.4 mo, respectively (HR=0.73; p=0.06). One-year PFS was 9.5 % for gem+placebo, compared with 21.5% for gem+nimo (HR=0.71; p=0.05). Significantly, in pts ≥ 62 years (60% of the population), median OS and PFS were 5.2 mo in the gem+placebo group vs. 8.8 mo in gem+nimo (HR=0.66; p=0.034), and 3.2 in gem+placebo vs. 5.5 mo in gem+nimo group, respectively (HR=0.55; p=0.0096). Nimo was safe and well tolerated, and no grade 3/4 toxicities were observed. Thirteen % of pts experienced grade 1/2 skin toxicity. Conclusions: This randomized study clearly showed that nimo in combination with gem is safe and well tolerated. The 1-year survival rate is significantly improved. Especially pts ≥ 62 years seem to benefit, possibly due to a more aggressive biology in younger pts. Clinical trial information: NCT00561990.
SPARC in pancreatic cancer: Results from the CONKO-001 study.
Authors: Sinn Marianne , Sinn Bruno Valentin , Striefler Jana Kaethe , Stieler Jens , Pelzer Uwe , Prinzler Judith , Neuhaus Peter , Dietel Manfred , Dörken Bernd , Oettle Helmut , Riess Hanno , Denkert Carsten 
Published: March 2020

4016 Background: Previous investigations in pancreatic cancer suggested an important prognostic role for SPARC (secreted protein acidic and rich in cysteine) expression in the peritumoral stroma but not for cancer-cell cytoplasmic SPARC expression. So far no data from prospective studies in patients after curatively intended surgery are available. Methods: CONKO-001, a prospective randomized phase III study, investigated the role of adjuvant gemcitabine as compared to observation. Tissue samples of 160 patients were collected and analysed by immunohistochemistry for the expression of SPARC in the peritumoral stroma (strong versus not strong [=moderate to negative]) and in the tumor cell cytoplasm (immunoreactive score IRS 0-12, 0-2 = negative, 3-12 = positive) by a pathologist blinded to clinical outcome. Kaplan-Meier analyses for disease-free survival (DFS) and overall survival (OS) were performed in dependence of SPARC expression. Results: Strong stromal SPARC expression was associated with worse DFS and OS in the overall study population (strong vs not-strong DFS 9.0 vs 12.6 months, p=0.005; OS 19.8 vs 26.6 months (p=0.033). It was highly prognostic in the subgroup treated with gemcitabine (strong vs not-strong DFS 12.1 vs. 18.4 months; p=0.007, OS 17.9 vs 30.2 months, p=0.006), but not in the observation group (strong vs not strong DFS 6.6 vs 7.3 months p=0.767; OS 21.5 vs 18.2 months, p=0.765). Cytoplasmic SPARC expression in the adenocarcinoma cells was also associated with worse patient outcome (positive vs negative DFS 7.4 vs 12.1 months, p=0.041; OS 14.1 vs 25.6 months, p=0.011), again the effect was restricted to patients treated with gemcitabine (positive vs negative DFS 8.3 vs 15.3 months, p=0.002; OS 11.0 vs 28.8 months, p= 0.003; control group DFS 5.8 vs 7.6 months, p=0.844; OS 14.9 vs 20.8 months, p=0.519). Conclusions: Our data confirm the prognostic significance of SPARC expression and demonstrate a significant prognostic factor of SPARC in patients with pancreatic cancer after curatively intended resection. The prognostic impact was restricted to patients who received adjuvant treatment with gemcitabine. In difference to former published data this was found for peritumoral SPARC as well as for SPARC expression in tumor cells.
Clinical outcome according to tumor HER2 status and EGFR expression in advanced gastric cancer patients from the EXPAND study.
Authors: Lordick Florian , Kang Yoon-Koo , Salman Pamela , Oh Sang Cheul , Bodoky Gyorgy , Kurteva Galina Petrova , Volovat Constantin D. , Moiseyenko Vladimir , Sawaki Akira , Park Joon Oh , Gorbunova Vera A. , Goette Heiko , Melezinkova Helena , Stroh Christopher , Moehler Markus 
Published: March 2020

4021 Background: In the EXPAND study adding cetuximab to first-line capecitabine and cisplatin chemotherapy (CT) failed to improve clinical outcome in patients (pts) with advanced gastric or gastroesophageal junction cancer. This analysis assessed treatment outcome according to tumor HER2 status (a pre-defined subgroup) and EGFR expression in EXPAND study pts. Methods: Tumor HER2 status was determined primarily by immunohistochemistry (IHC), HER2 +ve tumors were IHC 3+ or IHC 2+ and fluorescence in situ hybridization (FISH) +ve. EGFR expression was assessed by IHC. A continuous scoring system (scale of 0–300) was used to determine the level of EGFR expression. Biomarker status was correlated with clinical outcome. Results: In both treatment arms, pts with HER2 +ve tumors (n=144) vs HER2 -ve tumors (n=535) had a longer median overall survival (OS): 13.3 (95% CI 10.9–15.5) vs 9.2 (95% CI 8.1–10.5) months in the CT + cetuximab arm and 14.0 (95% CI 11.3–17.1) vs 9.7 (95% CI 8.6–11.0) months in the CT arm, and a better overall response rate, 51.4 (95% CI 39.3–63.3) vs 27.0 (95% CI 21.9–32.6) % and 37.5 (95% CI 26.4–49.7) vs 26.4 (95% CI 21.1–32.3) % respectively. In stepwise multivariable models, pts with HER2 -ve vs HER2 +ve tumors showed an increased risk of death (adjusted hazards ratio 1.552, 95% CI 1.244–1.936) and reduced odds of response (adjusted odds ratio 0.477, 95% CI 0.316–0.720). EGFR tumor expression was evaluable in 774 pts from the intent to treat population (n=904). The EGFR IHC score was low (median 0, range 0–300). No discriminating threshold for the IHC score was identified. However in pt subgroups defined by a series of cut-off points from an IHC score of 10 upwards (rising incrementally by 10), there was a tendency for improved OS, progression-free survival, and tumor response when adding cetuximab to CT in pts with high tumor EGFR IHC scores. Conclusions: In this analysis of EXPAND study pts, those with HER2 +ve tumors were associated with better outcome irrespective of the treatment arm compared with pts with HER2 -ve tumors. Tumor EGFR expression was generally low. Adding cetuximab to CT failed to improve outcome overall, but may benefit a small proportion of pts with high EGFR tumor expression. Clinical trial information: 2007-004219-75.
Placebo controlled, double blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors (PROMID): Results on long-term survival.
Authors: Arnold Rudolf , Wittenberg Michael , Rinke Anja , Schade-Brittinger Carmen , Aminossadati Behnaz , Ronicke Erdmuthe , Gress Thomas Mathias , Mueller Hans Helge ,   PROMID Study Group
Published: March 2020

4030 Background: Octreotide LAR (O) compared to placebo (P) lengthens significantly time to tumor progression (TTP) in patients with metastatic midgut neuroendocrine tumors (Rinke et al. 2009). The antiproliferative response was more pronounced in patients with low (≤ 10%) hepatic tumor load (HL). To investigate whether this beneficial effect also affects overall survival (OS), patients included in the PROMID trial were followed until January 2013 at least once a year. Methods: Between July 2001 and January 2008, 42 and 43 patients were randomly assigned to receive O or P. Post study treatment was at the discretion of the local investigator. Data on cause of death and on post study treatment were documented. OS was analyzed using the Kaplan-Meier method. Treatment groups (O vs. P; HL at study entry ≤ 10% vs. >10%) were compared using the log rank test and hazard ratios were estimated with the use of the Cox proportional hazards model. Results: 41 of 85 patients died until January 2013. 19 in the octreotide and 22 in the placebo arm. Median OS for all 85 patients was 85 months, “not reached” in the O arm and 84 months in the P arm (p=0.59, HR=0.85 [CI 0.46; 1.56]). Cause of death was unrelated to the tumor disease in 8 patients. 26 of 64 patients (10 in the O vs. 16 in the P arm) died in the HL ≤ 10% subgroup and 15 of 21 patients (9 in the O vs. 6 in the P arm) in the HL > 10 % (p=0.002, HR=2.7). Median OS in the HL ≤ 10% subgroup was “not reached” (octreotide) vs 80.5 months (placebo) (p=0.14, HR=0.56 [CI 0.25; 1.23]). In the HL > 10% subgroup the respective numbers were 35 vs. 84 months (p=0.14, HR=2.18 [CI 0.75; 6.33]). Post study treatment in the O and P groups included octreotide LAR (29 vs. 38 patients), hepatic CHE (5 vs. 12 patients), PRRT (13 vs. 13 patients) and CHT (4 vs. 5 patients). Conclusions: Octreotide LAR not only prolongs TTP but also extends OS in the subgroup of patients with metastatic midgut NETs and a low HL (≤ 10% at study entry) but not in the high (HL > 10%) subgroup. Almost all patients who were randomized at study entry in the P group received octreotide LAR after disease progression, but these experienced a less favourable OS in the low HL subgroup. Clinical trial information: NCT00171873.