bluuebunny/crossref_metadata_2025 huggingface dataset:
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 .
Outcome analyses in patients with metastatic gastroenteropancreatic neuroendocrine tumors receiving peptide receptor radionuclide therapy with 177Lu-DOTATATE – Impact of treatment order and combination on mortality.
Authors: Siebenhuener Alexander Rheinhard , Pretot Dominique , Treyer Valerie
Published: May 2020

4606

Background: Neuroendocrine tumors of the gastroenteropancreatic tract present heterogeneous with several systemic treatment options in the advanced setting. PRRT with 177Lu-DOTATATE targeting the SSTR-2 receptor of these tumors showed effective responses in the NETTER-1 trial in the short as well as long term follow-up of patients. The aim of our study was to determine the HRQoL and outcome of GEP-NET patients. Methods: 41 GEP-NET patients who received 177Lu-DOTATATE (mean: 3 cycles) between 2012 and 2017 at University Hospital Zurich (USZ) were included in this retrospective analysis. HRQoL parameters (fatigue, insomnia, loss of appetite, abdominal pain, nausea, emesis, diarrhea, weight loss) were assessed before and after treatment. At least 3 weeks after the last PRRT cycle, data on blood parameters, HRQoL, and overall survival data were extracted from patient records. To determine factors influencing the success of PRRT therapy and survival, we recorded pre- and post-PRRT treatments (e.g. selective internal radiation therapy/SIRT, somatostatin analogue therapy/SSA, TKI or chemotherapy) and the time-point of PRRT in the therapeutic sequence was analyzed. Results: Baseline rates of HRQoL and ECOG performance status were assessed (baseline mean: ECOG 0). PRRT was well tolerated, with most patients reporting no significant deterioration in HRQoL after treatment. Blood parameters (hemoglobin, leucocyte and platelet counts, creatinine) and glomerular filtration rate were not significantly affected by PRRT therapy. The number of previous treatments did not influence survival after PRRT; neither did the length of the time period between first diagnosis and PRRT. Patients with a SIRT treatment prior to PRRT had an elevated mortality odds ratio of 4.083. If SIRT was applied to patients with a pancreatic tumor, the mortality odds ratio was 1.33 compared to patients without a pancreatic tumor. Post-PRRT SSA increased the odds for survival, with a mortality odds ratio of 2.33 for patients without SSA after PRRT. Conclusions: Patients with advanced GEP-NETs may benefit from PRRT with 177Lu-DOTATATE, as this treatment appears to be well tolerated and does not significantly impair the HRQoL or symptom load. SIRT before PRRT seems to lower the chances of response and reduces survival instead using this sequence vice versa. This trend was also seen if SSA was not used after PRRT. But these trends have to be proven in prospective trials.
Concordance between independent and investigator assessment of disease-free survival (DFS) in the APACT trial.
Authors: Reni Michele , Riess Hanno , O'Reilly Eileen Mary , Reeves James Andrew , Chiorean Elena , George Thomas J. , Scheithauer Werner , Pascal Artru , Lerch Markus , Brenner Warren S. , Ko Yoo-Joung , Tabernero Josep , Van Cutsem Eric , Philip Philip Agop , Goldstein David , Berlin Jordan , Biankin Andrew , Tempero Margaret A.
Published: May 2020

4618

Background: APACT was a phase III trial of adjuvant nab-paclitaxel + gemcitabine ( nab-P + Gem) vs Gem alone in patients with resected pancreatic cancer (PC) and the first adjuvant PC trial to use independently assessed DFS as the primary endpoint (DFS by investigator review was a prespecified sensitivity analysis). We examined concordance between independent and investigator DFS review. Methods: For the independent assessment, reviewers determined recurrence by computed tomography or magnetic resonance imaging but were blinded to treatment and clinical data. Investigator-assessed DFS was based on all available data. Concordance was summarized by κ statistics. Patients who did not have recurrence or were alive were censored at the last tumor assessment date with disease-free status or the randomization date if the last tumor assessment with disease-free status was missing. Patients who received new anticancer therapy or cancer-related surgery prior to recurrence or death were censored at the date of last tumor assessment with disease-free status prior to the start of new anticancer therapy or cancer-related surgery or the randomization date if the last tumor assessment date with disease-free status prior to the start of subsequent new anticancer therapy or cancer-related surgery was missing. All censoring rules were the same for analysis of DFS by independent and investigator review. Results: Median DFS by independent review was 19.4 ( nab-P + Gem) vs 18.8 (Gem) months (hazard ratio [HR] 0.88; 95% CI, 0.73 - 1.06; P = 0.18); median investigator-assessed DFS was 16.6 ( nab-P + Gem) vs 13.7 (Gem) months (HR 0.82; 95% CI, 0.69 - 0.97; nominal P = 0.017). Moderate concordance was found between independent- and investigator-assessed DFS (Table); similar results were observed in the nab-P + Gem (concordance, 78%; κ coefficient, 0.56) and Gem alone (concordance, 76%; κ coefficient, 0.53) arms. Conclusions: The results reflect the complexities of defining the recurrence timepoint accurately and suggest that radiological review in the absence of clinical context is suboptimal for recurrence detection in resected PC. These findings may inform future clinical trial design. Registration: EudraCT (2013-003398-91); ClinicalTrials.gov (NCT01964430). Clinical trial information: NCT01964430 . [Table: see text]
Real-life results from the prospective QoliXane trial of the platform for outcome, quality of life, and translational research on pancreatic cancer (PARAGON) registry.
Authors: Al-Batran Salah-Eddin , Hofheinz Ralf Dieter , Reichart Alexander , Pauligk Claudia , Schlag Rudolf , Siegler Gabriele Margareta , Hoeffkes Heinz-Gert , Blau Wolfgang , Homann Nils , Trojan Jorg , Waidmann Oliver , Pink Daniel , Messmann Helmut , Kunzmann Volker , Vogel Arndt , Ettrich Thomas Jens , Schoenherr Caroline , Schaaf Marina , zur Hausen Gerrit , Goetze Thorsten Oliver
Published: May 2020

4625

Background: Gemcitabine and nab-paclitaxel (NPG) is standard first-line therapy for metastatic pancreatic cancer (mPC), but the pivotal study did not include quality of life (QoL) analyses. Methods: The QOLIXANE-PARAGON study started as a prospective, non-interventional, multicenter study conducted in Germany and transitioned into a permanent registry for pancreatic cancer patients (pts) considering all types of treatments. This report focuses on the pts enrolled into the QOLIXANE portion of the study. Pts were recruited from 95 German centers. QoL was prospectively measured via EORTC-C30 questionnaires (prior to and every month thereafter): therapy and efficacy parameters were prospectively collected. QoL and efficacy endpoints were analyzed in the intention-to-treat population (ITT). The primary endpoint was the rate of pts without deterioration of QoL/Global Health Score (QoL/GHS) at 3 months. Results: 600 pts were enrolled. Mean GHS/QoL score at baseline was low and was 46.2 (SD 22.8). Median progression-free survival was 5.85 months (95% CI, 5.23 to 6.25). Median overall survival (OS) was 8.91 months (95% CI, 7.89 to 10.19). The KM-analysis showed that 61% and 41% of pts had maintained QoL/GHS after 3 and 6 months, respectively. Median time to deterioration of QoL/GHS was 4.68 months (95% CI, 4.04 to 5.59). Mean QoL/GHS improved from 46.1 (SD 22.7) at baseline to 52.8 (SD 21.3) after 6 months. In the QoL response analysis, 34.6%, 37.4% and 28% of evaluable pts had improved, stable and worse QoL/GHS after 3 months, respectively. In the Cox regression analysis, GHS/QoL scores strongly predicted survival with a HR of 0.86 (p < 0.0001). Conclusions: QoliXane the largest study on QoL of mPC. It shows that time to deterioration of QoL is short but that a relevant group of mPC in first line have improved or maintained QoL after 3 and 6 months and that QoL is a predictor of pts outcome. Clinical trial information: NCT02691052 .
Pharmacokinetically-guided 5-FU dose optimization within the preoperative FOLFOXIRI regimen in resectable pancreatic cancer patients.
Authors: Vilalta Anna , Urrizola Martínez Amaia , Aldaz Azucena , Sala Elarre Pablo , Ponz-Sarvisé Mariano , Rotellar Fernando , Pardo Fernando , Subtil Jose Carlos , Chopitea Ana , Rodriguez Javier
Published: May 2020

4636

Background: Neoadjuvant therapy is an increasingly used approach in patients with resectable pancreatic cancer (PC). A positive link between chemotherapy dose intensity and patients’ outcome has been suggested in PC. The aim of this study was to rule out whether 5-FU pharmacokinetic (PK) parameters correlate with outcome in resectable PC patients treated with preoperative FOLFOXIRI. Methods: Patients with resectable and borderline resectable PC treated with Oxaliplatin (85mg/m2), Leucovorin (400mg/m2), Irinotecan (150 mg/m2) and 5-FU (initial dose of 3200 mg/m2 in 46h infusion and subsequent doses based on PK-guided dose adjustements targeting an AUC of 25-30 mcg*h/ml) were included. 5-FU PK analysis was performed taking two plasma samples during 5-FU infusion in at least two cycles. Drug concentrations were analysed by High-Perfomanced Liquid Chromatography. After induction polychemotherapy (IPCT), patients with no progressive disease received chemoradiation (CRT) (50.4 Gy with concurrent Capecitabine and Oxaliplatin) followed by surgical resection 4 to 6 weeks after the completion of CRT. Subsequent follow-up until disease progression was remained. An exploratory analysis with Log-Rank test was performed to assess progression free survival (PFS) based on 5-FU AUC values. Results: From November 2012 to October 2018, 29 patients were retrospectively assessed: median age 63 (46-75); M/F rate 20/9; R0 resection rate of 90% in the intention-to-treat analysis. The pathological response according to CAP classification was 0, 1, 2 and 3 in 14, 58, 19.5 and 8.5%, respectively; and median number of resected lymph nodes was 11 (2-22), with lymph node infiltration (ypN1) in 14% of patients. Grade 3-4 IPCT related toxicities and grade 3 CRT related toxicities were reported in 40 and 30% of patients, respectively. Median PFS was 723 days (24 months) and median 5-FU AUC 28.5 mcg*h/ml (23-53). Median PFS for patients with 5-FU AUC ≥27 mcg*h/ml was 29 months versus 15 months in patients with 5-FU AUC < 27 mcg*h/ml (adjusted hazard ratio for disease progression 0.223; 95% CI = 0.059-0.848; p = 0.028; in a model controlled by age, sex and irinotecan dose intensity). Conclusions: 5-FU pharmacokinetic parameters achieving a target of AUC ≥ 27 mcg*h/ml seem to correlate with longer PFS in this subset of patients.
Cobimetinib plus gemcitabine is an active combination in KRAS G12R-mutated in previously chemotherapy-treated and failed pancreatic patients.
Authors: Ardalan Bach , Cotta Jared Addison , Gombosh Miriam , Azqueta Jose Ignacio
Published: May 2020

4642

Background: he KRAS proto-oncogene is involved in the RAS/MAPK pathway. Various G12X mutations have been examined with the most common mutations being G12D (40%), G12V (30%), and G12R (15-20%) in pancreatic cancer patients. Throughout the course of studying the G12X mutations, we have observed that not all KRAS mutations are equal. Preclinical data shows G12R is impaired in pI3Kα signaling, as compared to KRAS G12V/D. This mechanism is important in PDAC as it allows tumor growth to be sustained. In preclinical studies, PDX derived tumors were transplanted in mice and were treated with a MEK inhibitor plus chemotherapy, which demonstrated a greater tumor regression than either agent alone. Therefore, we have decided to treat patients with Gemcitabine alongside a 2nd generation MEK inhibitor (Cobimetinib). Methods: In our single arm study, 13 KRAS mutated pancreatic patients (KRAS G12D, G12V, and G12R) received the combination of Cobimetinib 20mg BID weekly for three weeks alongside Gemcitabine at 1000mg/m2 weekly, followed by one week of rest. The above constitutes one cycle. Results: Patients were divided into two groups; Group 1 consists of seven patients that were KRAS G12D/G12V mutated, and Group 2 included six KRAS G12R mutated patients. In Group 1, seven patients on treatment progressed and died within two months on the study. In Group 2, one achieved PR and others stable disease. Median progression-free survival was 6.0 months (95% CI 3-9.3 months) and median OS has not been reached. All patients are alive at 8 months. Common adverse reactions include rash, fatigue, nausea, and vomiting. Cancer antigen 19-9 decreased in ≥ 50 of all patients in the latter group. We would like to report our positive study to the society. Moreover, we intend to confirm the study in a larger patient cohort. Conclusions: Pancreatic cancer patients that demonstrate KRAS G12R mutations are treatable with a new active combination chemotherapy.
A pilot study to determine the feasibility of a customized low glycemic load diet in patients with stage I-III colorectal cancer.
Authors: Treasure Michelle Elizabeth , Thomas Alicia , Ganocy Stephen , Hong Augustine , Krishnamurthi Smitha S. , Bajor David Lawrence , Berger Nathan A. , Meropol Neal J.
Published: May 2020

4643

Background: Observational evidence associates energy balance factors, particularly diet, with survival in patients with colorectal cancer (CRC). Consumption of a diet with high glycemic indices has been associated with inferior cancer-specific outcomes, but there is limited prospective evidence that alterations in dietary habits improve cancer outcomes. This was a pilot study to determine the feasibility and acceptability of following a low glycemic load (GL) diet in patients with stage I-III CRC and to assess the nutritional resources necessary to follow the diet. Methods: 18 patients with stage I-III CRC, who completed definitive cancer therapy and consumed an avg daily GL > 150 participated in a 12 week, tailored, in-person dietary intervention with a target GL of ≤102. Compliance was assessed using 24 hour telephone recalls. Acceptability of the diet was assessed using a food acceptability questionnaire, and exploratory correlative laboratories were assessed monthly. Results: 67% of patients were compliant with a low GL diet ≥ 75% of the time, over a 12 week time period. Majority of participants experienced a decrease in BMI and waist circumference, 28% experienced meaningful weight loss defined as ≥ 5%. The nutritionist spent an avg of 6.97 hours (SD 2.18) in-person and 1.58 hours (SD 0.68) by phone with each participant. In the overall group, significant decreases were seen in total cholesterol (7.2% decrease; t = -2.33, p = 0.03), VLDL (26.8% decrease; t = -2.33, p = 0.03) and triglycerides (26.6% decrease; t = -2.29; p = 0.04). All participants were satisfied with the diet; 43% were extremely satisfied. 75% of participants liked the foods they were able to eat “very much” or “extremely”. All participants felt the in-person meetings were helpful. 77% did not feel an online video could replace the in-person meetings. 62% of participants did not feel a virtual meeting (e.g skype, etc.) could replace the in- person meeting while 38% felt it could. Conclusions: Patients with stage I-III CRC are able to follow a low GL diet with an in-person dietary intervention. Significant decreases in laboratory measures confirm the efficacy of the diet in altering metabolic indices. All participants who completed the study were satisfied with the diet, the majority of whom enjoyed the foods and planned to continue to follow the diet after study completion. The majority felt in-person contact with the nutritionist was essential to their success. This study was an essential step in designing a larger scale trial to evaluate the impact of low GL diet on cancer outcomes. Clinical trial information: NCT02129218 .
Adjuvant chemoradiotherapy impact on the overall survival of completely resected ampullary and periampullary carcinoma: An updated meta-analysis.
Authors: Haddad Philip A. , Gallagher Kevin M. , Hammoud Dalia A.
Published: May 2020

4645

Background: Ampullary and Periampullary carcinomas (APAC) are uncommon gastrointestinal cancers that are often amenable to surgical resection. The benefit of postoperative adjuvant chemoradiotherapy (ACRT) in patients with completely resected localized AC has been controversial. A meta-analysis which was conducted in 2017 found no associated survival benefit for adjuvant therapies in APAC. However, this meta-analysis was methodologically flawed and combined studies that used adjuvant chemotherapy alone with those that used ACRT. The purpose of this meta-analysis is to evaluate the impact of ACRT on the overall survival (OS) of patients with completely resected APAC incorporating more recent studies. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of resected Ampullary and Periampullary carcinoma, English language, publications from 1999 to the present, comparative studies reporting OS with hazard ratios (HR) or Kaplan-Meier curves of patients that underwent ACRT versus those that did not, and studies that reported the aggregate OS data of adjuvant therapies where the preponderance of the cohort received ACRT. Adjuvant chemotherapy studies and those that reported aggregate OS for a cohort with preponderance of adjuvant chemotherapy were excluded. A meta-analysis was conducted using an inverse variance method with a random-effects model. Results: Sixteen retrospective series with a total of 1122 patients were included and analyzed. The majority of APAC patients that received ACRT tended to have high risk features. Four of these studies analyzed their OS data for the high risk APAC patients in addition to the cohort as a whole. Intra-arterial chemotherapy and concomitant radiotherapy was used in one study. ACRT was found to be significantly associated with better OS in patients with completely resected APAC (HR 0.76, 95%CI: 0.65-0.88, p < 0.001). Conclusions: This is the first meta-analysis to show that adjuvant chemoradiotherapy is associated with a survival benefit in patients with completely resected high risk Ampullary and Periampullary carcinoma. In the absence of randomized clinical trials, this meta-analysis represents the most compelling data supporting the use of ACRT in this patient population.
Biomarker analyses from the phase III CheckMate 214 trial of nivolumab plus ipilimumab (N+I) or sunitinib (S) in advanced renal cell carcinoma (aRCC).
Authors: Motzer Robert J. , Choueiri Toni K. , McDermott David F. , Powles Thomas , Yao Jin , Ammar Ron , Papillon-Cavanagh Simon , Saggi Shruti S. , McHenry Brent M. , Ross-Macdonald Petra , Wind-Rotolo Megan
Published: May 2020

5009

Background: In CheckMate 214 (NCT02231749), N+I demonstrated superior clinical outcomes vs S in patients (pts) with aRCC. Here, we report exploratory biomarker analyses of pretreatment tumor samples relative to outcomes. Methods: Formalin-fixed, paraffin-embedded aRCC samples were characterized by immunohistochemistry (tumor programmed death ligand 1 [PD-L1], n = 992; PD-L1 combined positive score [CPS], n = 980), whole exome sequencing (WES; tumor mutational burden, indel burden, HLA class I zygosity, and PBRM1 mutation status; n = 481), and RNAseq (n = 213). Gene signature scores were calculated as the median value of Z-scored expression for transcripts. Association with outcome was tested using Fisher’s exact test and Cox proportional hazards model. With ≥ 42 mo follow-up, prolonged progression-free survival (PFS) with N+I ( < or ≥ 18 mo; n = 82 vs 27, respectively) was analyzed by limma and gene set enrichment analysis of Hallmark gene sets (MSigDB). Results: PD-L1 CPS did not have improved predictive power over tumor PD-L1. The WES-derived biomarkers were not associated with outcomes in pts treated with N+I or S. For the RNAseq cohort, objective response rates (ORR) for pts with ≥ median scores, and hazard ratios (HR) relative to < median are shown (Table). A higher angiogenesis (Angio) gene signature score was associated with higher ORR and PFS for S; lower Angio score was associated with higher ORR in N+I. Immune signature scores were not predictive for ORR in N+I. Prolonged PFS with N+I (≥ 18 mo, n = 27) was associated with higher expression of Hallmark inflammatory response and Hallmark epithelial mesenchymal transition (EMT) gene sets (both adjusted P = 0.002). Conclusions: The Angio gene signature was associated with ORR for S (high score) and N+I (low score). Prolonged PFS in 27 pts receiving N+I was linked with inflammation (consistent with findings from PD-1 blockade monotherapy), but associated with EMT-related transcripts (in contrast with findings in other tumor types). Further validation of these exploratory analyses will be required. Clinical trial information: NCT02231749 . [Table: see text]
Association of gene expression with clinical outcomes in patients with renal cell carcinoma treated with pembrolizumab in KEYNOTE-427.
Authors: McDermott David F. , Lee Jae-Lyun , Donskov Frede , Tykodi Scott S. , Bjarnason Georg A. , Larkin James M. G. , Gafanov Rustem , Kochenderfer Mark D. , Malik Jahangeer , Poprach Alexandr , Signoretti Sabina , Cristescu Razvan , Predoiu Raluca Andreia , Loboda Andrey , Zhang Yiwei , Zhao Qing , Snyder Alexandra , Schloss Charles , Perini Rodolfo F. , Atkins Michael B.
Published: May 2020

5024

Background: We assessed the association of baseline RNA-sequencing–based gene expression signatures and DNA alterations with response or resistance to pembrolizumab in patients with advanced renal cell carcinoma in cohorts A (clear cell; n = 110) and B (non-clear cell; n = 165) of the phase 2 KEYNOTE-427 study (NCT02853344). Methods: Using RNA-sequencing, we analyzed the association of gene expression signatures (18-gene T-cell–inflamed gene expression profile [GEP]; 10 non–T-cell–inflamed GEP canonical signatures [angiogenesis, gMDSC, glycolysis, hypoxia, mMDSC, MYC, proliferation, RAS, stromal/EMT/TGFβ, WNT]) quantifying tumor microenvironment elements (TME) with objective response rate (ORR) and progression-free survival (PFS). Canonical signatures were derived from 2 databases (TCGA, Moffit) using an algorithm that included genes based on their correlation to reference signatures in the literature. Signature definitions were finalized before linking to the clinical data, and significance was prespecified at 0.10 given the potential for limited power. Canonical signatures were analyzed through regression testing of response for association with consensus signatures after adjusting for T-cell–inflamed GEP and International Metastatic RCC Database Consortium scores in the model. P values were adjusted for multiplicity. Using whole exome sequencing, we also summarized the association of renal cell carcinoma driver gene mutations with ORR. Clinical data cutoff: Jan 30, 2019. Results: Patient characteristics for this analysis were comparable to the overall population. In cohort A, T-cell–inflamed GEP (n = 78) was statistically significantly associated with a better ORR ( P = 0.021; AUROC = 0.65) but not PFS ( P = 0.116). No other TME canonical signatures showed a correlation with ORR or PFS. ORR was estimated for mutations (Table). Conclusions: RNA-sequencing–based, T-cell–inflamed GEP was associated with ORR in patients with clear cell renal cell carcinoma receiving first-line pembrolizumab. Precision was limited by sample size for estimating ORR by specific gene mutation status. Evaluation of tissue-based biomarkers in larger studies are planned. Biomarker analyses from patients in cohort B will also be presented. Clinical trial information: NCT02853344 . [Table: see text]
Early response marker during pembrolizumab treatment in metastatic urothelial cancer: Temporal shift in peripheral CD4 T cells expressing chemokine receptors.
Authors: Rijnders Maud , Balcioglu Hayri Emrah , Robbrecht Debbie , Boormans Joost L. , Aarts Maureen J.B. , Hamberg Paul , Voortman Jens , Westgeest Hans , De Wit Ronald , Lolkema Martijn P. , Van Der Veldt Astrid Aplonia Maria , Debets Reno
Published: May 2020

5033

Background: Approval of PD1 blockade greatly improved treatment possibilities for patients with platinum-resistant metastatic urothelial cancer (mUC), however the current response rate for pembrolizumab is less than 25%. Since PD-L1 expression does not have predictive value in this setting, the aim of this study was to identify new markers to improve patient selection. Methods: Between Sept 2017 and Jan 2020, 84 mUC patients received pembrolizumab in a prospective biomarker discovery study (NCT03263039). Peripheral blood samples (n = 22) taken prior to and at 6 and 12 weeks after start of treatment were analyzed for frequencies of CD4 and CD8 T cells expressing co-inhibitory, co-stimulatory and chemokine receptors using multiplex flow cytometry. Plasma chemokine levels were determined using ELISA (n = 38), and fresh tumor biopsies obtained prior to and during treatment (n = 26) were analyzed for densities and phenotypes of T cells using multiplex immunofluorescence staining. T cell receptor clonality was analyzed in peripheral blood (n = 10) and tumor biopsies (n = 6) using RNA sequencing. Patients were classified as responder (complete or partial response) or non-responder (progressive disease) according to RECIST v1.1 after 12 weeks of treatment. Results: Longitudinal sampling revealed that upon treatment the frequency of CXCR3+ CD4 T cells decreased in responders, whereas the frequency of CXCR3+ CCR1+ CD4 T cells drastically increased in non-responders. Before treatment, the frequency of CD4 T cells co-expressing CXCR3 and CCR1 was already decreased in responders. Notably, in responders, the treatment-related decrease in frequency of CD4 T cells expressing chemokine receptors was accompanied by a decrease in the frequency of CD4 T cells expressing the co-inhibitory receptor PD1, whereas an increase in the frequency of CD4 T cells expressing the co-stimulatory receptor 4-1BB was observed. These findings will be complemented with chemokine levels in plasma, contexture of T cells in tumor biopsies, and T cell receptor clonality analysis. Conclusions: mUC patients responding to pembrolizumab treatment demonstrated an on-treatment decrease in frequency of CD4 T cells expressing chemokine receptors that is accompanied by a changed frequency of co-signaling receptor expressing CD4 T cells. These data show that dynamic immune phenotyping can distinguish effective from less effective immune activation by pembrolizumab, and may provide early markers for benefit from PD1 blockade in mUC patients.
Atezolizumab (atezo) therapy for locally advanced/metastatic urinary tract carcinoma (mUTC) in patients (pts) with poor performance status (PS): Analysis of the prospective global SAUL study.
Authors: Castellano Daniel , Gedye Craig , Fornarini Giuseppe , Fay Andre P. , Voortman Jens , Mego Michal , Bamias Aristotelis , Lester Jason Francis , Huddart Robert A , Matouskova Michaela , Gurney Howard , Mellado Begona , Ong Michael , Carneiro Filipa , Seseke Florian , Milesi Laura , Shariat Shahrokh F. , Fear Simon , de Ducla Sabine , Sternberg Cora N.
Published: May 2020

5035

Background: Pts with PS > 1 have a poor prognosis and are often excluded from clinical trials. The single-arm SAUL study (NCT02928406) evaluated atezo in a ‘real-world’ population. Overall, safety and efficacy were consistent with prior trials. However, ECOG PS 2 pts had worse overall survival (OS) but fewer adverse events (AEs) than ECOG PS 0/1 pts [Sternberg, 2019], likely reflecting shorter treatment duration and warranting exploration. Methods: Pts with mUTC received atezo 1200 mg q3w until loss of clinical benefit or unacceptable toxicity. The primary endpoint was safety. Post hoc analyses compared baseline factors, AEs and efficacy in pts with ECOG PS 2 vs 0/1. In this analysis, AE incidences were restricted to the first 45 days of atezo to adjust for differing treatment exposure. Results: None of the baseline factors explored was significantly associated with worse OS or disease control rate (DCR) in ECOG PS 2 pts. However, pts with visceral metastases and ECOG PS 2 had particularly poor outcomes. Safety appeared similar between subgroups. Conclusions: ECOG PS 2 pts have a dismal prognosis. The higher proportion with poor prognostic factors despite similar age in ECOG PS 2 vs 0/1 pts may suggest that poor PS was related to disease rather than comorbidities. Risk/benefit should be considered especially carefully when treating pts with ECOG PS 2 due to high-burden/visceral disease. Clinical trial information: NCT02928406 . [Table: see text]
Impact of renal impairment on clinical outcomes in patients (pts) with locally advanced or metastatic (LA/M) urinary tract carcinoma (UTC) treated with atezolizumab (atezo): Analysis of the international SAUL study.
Authors: Retz Margitta , Seseke Florian , Banna Giuseppe Luigi , De Giorgi Ugo , Powles Thomas , Basso Umberto , McDermott Raymond S. , Llado Anna , Su Wen-Pin , Cebotaru Cristina Ligia , Puente Javier , Montesa Alvaro , De Greve Jacques , Kahan Zsuzsanna , Anido Herranz Urbano , de Ducla Sabine , Pavlova Julie , Fear Simon , Sternberg Cora N.
Published: May 2020

5036

Background: Atezo, which targets PD-L1, is an approved therapy for LA/M urothelial carcinoma based on the IMvigor210 and IMvigor211 trials. The single-arm SAUL study (NCT02928406) showed consistent activity and safety in a broader population, including understudied scenarios, eg pts with renal impairment or other IMvigor211 exclusion criteria. Methods: Pts with LA/M UTC received atezo 1200 mg q3w until disease progression or unacceptable toxicity. The primary endpoint was safety; secondary endpoints included overall response rate (ORR) and overall survival (OS). Post hoc analyses explored outcomes in pts classified as: chemotherapy (CT) ineligible (calculated creatine clearance [CrCl] 15– < 30 mL/min); cisplatin ineligible and carboplatin eligible (CrCl 30– < 60 mL/min); or cisplatin eligible (CrCl ≥60 mL/min). Results: Of 1004 enrolled pts, 46 (5%) were classified as CT ineligible and 420 (42%) as cisplatin ineligible. Results are summarized below. Conclusions: These post hoc analyses suggest pts typically considered cisplatin or CT ineligible are candidates for atezo. Pts with renal impairment achieved similar ORR and DCR to pts with CrCl ≥60 mL/min, without increased toxicity. Imbalances in pt characteristics may explain numerical differences in OS. Clinical trial information: NCT02928406 . [Table: see text]
Ipilimumab challenge/re-challenge in metastatic urothelial carcinoma (mUC) and other genitourinary (GU) tumors treated with cabozantinib+nivolumab (CaboNivo) or cabozantinib+nivolumab+ipilimumab (CaboNivoIpi).
Authors: Niglio Scot Anthony , Girardi Daniel da Motta , Mortazavi Amir , Lara Primo , Pal Sumanta K. , Saraiya Biren , Cordes Lisa M. , Ley Lisa , Sierra Ortiz Olena , Cadena Jacqueline , Diaz Carlos , Bagheri Mohammadhadi H. , Steinberg Seth M. , Costello Rene , Streicher Howard , Wright John , Parnes Howard L. , Ning Yang-Min , Bottaro Donald P. , Apolo Andrea B.
Published: May 2020

5039

Background: We investigated challenging/re-challenging pts with ipilimumab (ipi) after progression on CaboNivo or CaboNivoIpi. Methods: In a phase I expansion study, patients with mUC post-platinum chemotherapy and other GU tumors patients who progressed on Cabo 40 mg daily plus nivolumab, 3 mg/kg every 21 days (CaboNivo) alone or with ipi, 1 mg/kg every 21 days for 4 cycles (CaboNivoIpi)-and achieved a PR or SD≥6 mo, were challenged/re-challenged with ipi, 1 mg/kg every 21 days for up to 4 cycles. Restaging scans were done every 6 wks for the first 12 wks, then every 8 wks and evaluated by RECIST 1.1. Results: In total, 24 patients were evaluated: 18 pts (8 UC (5 bladder and 3 upper tract), 4 clear cell renal cell carcinoma (RCC), 3 urachal adenocarcinoma (adeno), 2 bladder adeno, and 1 sarcomatoid clear cell RCC) who progressed on CaboNivo were challenged with ipi. In the challenge group, median (m) follow-up was 21.2 months. One pt achieved a PR in the LNs, but was found to have brain metastases before the next restaging, 13 had SD and 4 had PD. Median duration of PR or SD was 3.6 months (95% CI: 1.4 – 7.8 months). The mOS from start of ipi challenge was 13.9 months (95% CI: 5.8 months- not estimable); mPFS was 4.6 months (95% CI: 1.9 – 8.7 months). Grade 1/2 treatment related adverse events (AEs) occurred in all 18 pts (100%) and ≥Grade 3 (G≥3) AEs occurred in 11 pts (61%). The most common G≥3 AEs were hypophosphatemia (22%), hypertension (6%), adrenal insufficiency (6%), increased AST (6%), and ALT (6%). Six patients (3 bladder UC, 1 penile squamous cell (SCC) carcinoma, 1 urethral SCC, and 1 clear cell RCC with sarcomatoid features) who progressed on CaboNivoIpi were re-challenged with Ipi. On re-challenge, mfollow-up was 20.9 months. There were no PRs, 3 SDs and 3 PDs. mOS from start of re-challenge was 4.0 months (95% CI: 2.2 – 23.3 months) and mPFS was 1.9 months (95% CI: 1.1 – 2.6 months). Grade 1/2 treatment related AEs occurred in all 6 pts (100%) and ≥Grade 3 (G≥3) AEs occurred in 2pts (33%). G≥3 AEs included 1 hypertension (17%) and 1 hyperphosphatemia (17%). Conclusions: Ipi challenge/re-challenge showed low response rates in pts previously treated with CaboNivo or CaboNivoIpi. However, pts treated with CaboNivo who were challenged with ipi had a better OS than patients who had progressed on CaboNivoIpi and were re-challenged with ipi. Larger trials are warranted testing the ipi challenge in pts progressing on CaboNivo. Clinical trial information: NCT02496208 .