tbuckley/cabot-search huggingface dataset:
Cytoreductive nephrectomy (CN) in metastatic renal cancer (mRCC): Update on Carmena trial with focus on intermediate IMDC-risk population.
Authors: Arnaud Mejean, Simon Thezenas, Christine Chevreau, Karim Bensalah, Lionnel Geoffrois, Antoine Thiery-Vuillemin, Luc Cormier, Herve Lang, Laurent Guy, Gwenaelle Gravis, Frederic Rolland, Claude Linassier, Marc-Olivier Timsit, Laurence Albiges, Stephane Oudard, Thierry Lebret, jean-Marc Treluyer, Sandra Colas, Bernard Escudier, Alain Ravaud
Journal: Journal of Clinical Oncology (2019)

4508 Background: Carmena was a randomized phase III trial, testing the benefit of CN followed by sunitinib (arm A) vs sunitinib alone (arm B), with stratification by MSKCC risk groups in 450 mRCC patients. Based on this trial, CN is not anymore recommended in mRCC (NEJM, Mejean et al, 2018). However there are questions about which patients could still benefit from CN, especially in intermediate risk group. In the present study, we investigated different subgroups from the Carmena trial to answer these questions. Methods: Carmena trial was initially stratified according to MSKCC risk groups. For the purpose of this analysis, we reclassified the patients based on IMDC risk groups. We also analyzed patients with one metastatic site vs more than one, as well as patients with secondary nephrectomy in arm B. Overall survival (OS) was the primary endpoint. Results: With a updated median FU of 61.5 months (mo), the median OS by ITT analysis was 15.6 vs 19.8 mo in arm A and B respectively stratified on MSKCC (HR 0.933 ; 95% CI [0.76- 1.15]) / stratified on IMDC (HR 0.957 ; 95% CI [0.78- 1.18]). Using IMDC risk group factors, 58.6% patients were intermediate and 41.4 % were poor risk. When looking at intermediate risk group only, 48.1% had only one risk factor (interval between diagnosis and treatment &lt; 1y), with a median OS of 30.5 and 25.2 mo in arm A and B respectively (HR 1.24 [0.81 – 1.90]). By contrast, 51.9 % had two risk factors (mostly low hemoglobin, high corrected calcium or neutrophils), with a median OS of 16.6 and 31.2 mo in arm A and B respectively (HR 0.61 [0.41 – 0.91] p = 0.015). Regarding number of metastatic sites, 33% had only one metastatic site. Median OS was 23.6 and 22.7 mo in arm A and B respectively (HR 1.08 [0.75 – 1.57]. Finally, 40 patients had a secondary nephrectomy in arm B, with median OS of 48.5 mo [CI 95%: 27.9-64.4] vs 15.7 mo [CI 95%: 13.3-20.5] in patients who never had surgery. Conclusions: With longer FU, Carmena trial confirms that CN is not superior to sunitinib alone in ITT population, both with MSKCC and IMDC risk groups. However for patients with only one IMDC risk factor, CN might be beneficial. Number of metastatic site is not helpful to define good candidates for surgery. Finally, patients with secondary nephrectomy have very long OS, supporting this strategy. Clinical trial information: NCT00930033.
Identification of targetable molecular alterations in the NCI-COG Pediatric MATCH trial.
Authors: Donald Williams Parsons, Katherine A. Janeway, David Patton, Brent Coffey, Paul M. Williams, Stanley R. Hamilton, Anjan Purkayastha, Gregory J. Tsongalis, Mark Routbort, Julie M Gastier-Foster, Lauren Saguilig, Jin Piao, Todd Allen Alonzo, Stacey L. Berg, Elizabeth Fox, Peter C. Adamson, Margaret M. Mooney, Naoko Takebe, James V. Tricoli, Nita Seibel
Journal: Journal of Clinical Oncology (2019)

10011 Background: The screening protocol for the NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial detects tumor alterations that are used to assign patients with treatment-refractory or recurrent cancers to phase 2 treatment arms of molecularly-targeted therapies. Methods: Patients age 1 to 21 years old with treatment-refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders treated at U.S. based COG sites are eligible. DNA and RNA extracted from FFPE tumor samples are sequenced using an Oncomine cancer gene panel for detection of mutations, amplifications, and fusions. Loss of SMARCB1, SMARCA4, and PTEN expression is detected by immunohistochemistry. Lists of actionable mutations (aMOIs) based upon available clinical and pre-clinical data are used a priori to determine eligibility for treatment arms. Results: Between 7/24/17 and 12/31/18, 422 patients with a median age of 13 years (range 1-21) were enrolled from 93 COG sites. Solid tumors comprised 71% (n = 300) of diagnoses, CNS tumors 24% (n = 101) and lymphomas/histiocytoses 5% (n = 21). A tumor sample was submitted for 390 patients, sequencing was attempted for 370 (95%), and results were confirmed for 357 (92%). Median turn-around time was 15 days. An aMOI for at least one of the 10 current treatment arms was identified in 112 patients (29%, 95% CI 24%-33%); 95 patients (24%, 95% CI 20%-29%) were assigned to a treatment arm with 39 patients (10%, 95% CI 7%-13%) enrolled to date. The aMOI rate was similar in patients less than 12 years of age (35%) compared to patients 12 years and older (25%). Actionable MAPK pathway alterations were found in 11% of patients (n = 41), most often HRAS/ KRAS/ NRAS mutations (n = 16), BRAF mutations or fusions (n = 14), or NF1 mutations (n = 11). Other genes with recurrent aMOIs included SMARCB1 (n = 14), ALK (n = 8), CDK4 (n = 8), PIK3CA (n = 7), PTEN (n = 7), FGFR1 (n = 5), and BRCA1/BRCA2 (n = 5). Conclusions: Approximately one-quarter of patients with tumor submitted for Pediatric MATCH screening have been assigned to an investigational therapy, facilitating the evaluation of molecularly-targeted agents in biomarker-positive pediatric cohorts through a collaborative nationwide study. Clinical trial information: NCT03155620.
PACIFIC-2: Phase 3 study of concurrent durvalumab and platinum-based chemoradiotherapy in patients with unresectable, stage III NSCLC.
Authors: Jeffrey D. Bradley, Makoto Nishio, Isamu Okamoto, Michael David Newton, Leonardo Trani, Norah J Shire, Yu Gu, Philip A. Dennis, Ki Hyeong Lee
Journal: Journal of Clinical Oncology (2019)

TPS8573 Background: Durvalumab, a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80, is approved in the US, Japan and several other countries, for the treatment of patients (pts) with unresectable, stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent chemoradiotherapy (cCRT). These approvals were based on results from the phase 3 PACIFIC study, in which durvalumab was given 1–42 days after completion of definitive cCRT and significantly improved progression-free survival (PFS) vs placebo (median 16.8 vs 5.6 months; HR 0.52, 95% CI 0.42– 0.65; p&lt;0.001) and overall survival (OS) vs placebo (stratified HR 0.68; 99.73% CI 0.47–0.997; p=0.0025). Increasing evidence suggests additional benefit when anti-PD-1/PD-L1 therapies are administered alongside cCRT. The PACIFIC 2 study therefore aims to assess whether durvalumab plus cCRT provides additional benefit, in terms of PFS and objective response rate (ORR), compared with cCRT alone. Methods: PACIFIC 2 is a phase 3, randomized, double-blind, placebo-controlled, multicenter, international study. Approximately 300 pts with unresectable stage III NSCLC will be randomized (2:1) to receive either durvalumab (intravenous 1500 mg) every 4 weeks (q4w) + cCRT, or placebo q4w + cCRT. Eligible pts must have histologically or cytologically confirmed stage III disease; ECOG performance status 0 or 1; and life expectancy &gt;12 weeks at randomization. Pts who discontinue treatment will be followed for safety and OS. Primary endpoints are PFS and ORR (RECIST v1.1) assessed via blinded independent central review. Secondary endpoints include OS; OS at month 24; complete response (CR) rate; duration of response; disease control rate; time to death/distant metastases; time from randomization to second progression; safety; and symptoms, functioning and global health status. Pts with a CR, partial response or stable disease will continue to receive durvalumab or placebo until clinical or RECIST v1.1-defined disease progression, or until another discontinuation criterion is met. Study enrollment began in March 2018 and recruitment is ongoing. Clinical trial information: NCT03519971.
Sequence of anthracyclines and taxanes in the neoadjuvant chemotherapy of HER2-negative breast cancer: Experience of a Brazilian oncological center.
Authors: Daniel D’Almeida Preto, André Octavio Nicolau Sanches, Alison Wagner Azevedo Barroso, Alessandra Caroline Moretto Carbinatto, Ana Lima Veneziani, Georgia Kons, MARIA BUDIB, Maria Augusta Zaffari Safro, Gustavo Sanches Faria Pinto, Alan Felipe Bello Secco, Marina Moreira Costa Zorzetto, Domicio Lacerda, Carlos Eduardo Paiva, Cristiano de Pádua Souza
Journal: Journal of Clinical Oncology (2019)

e12105 Background: The best sequence of anthracyclines and taxanes in the neoadjuvant chemotherapy of HER2-negative breast cancer is still unknown. The aims of this study were to assess the impact of the sequence order in the pathological complete response (pCR) rate, and in the disease free survival (DFS) and overall survival (OS). Methods: We retrospectively reviewed 235 HER2-negative breast cancer women treated with neoadjuvant chemotherapy from 2003 to 2011 at our cancer center. The patients were pooled in two groups: anthracycline-based followed by taxanes (AC-T) and the reverse sequence (T-AC). The chi-square test was performed to verify the homogeneity between the groups and to compare pCR rate among the treatment groups. Cumulative survival probabilities were calculated using the Kaplan-Meier method. Differences between survivals were tested using the log-rank test. Results: The AC-T (n = 161) and T-AC (n = 74) groups were balanced for age, staging, receptor profile and histologic grade. The follow-up was at least five years for each patient. The median age was 50.1 years. Most patients (97%) had stage III tumors and 72 (30%) had triple negative disease. pCR rate was higher in triple negative compared with luminal cases (16.3 vs. 7.3%; p = 0.049). Treatment sequence did not influence the occurrence of pCR (10.5 vs. 8.5%; p = 0.8) or median survival times (DFS: 87.9 vs. 64.1, p = 0.85; OS: 91.1 vs. 71.6 months, p = 0.15), in the AC-T and T-AC groups, respectively. Conclusions: The sequence of neoadjuvant taxane-anthracycline-based chemotherapy regimen in daily practice did not show difference in the evaluated clinical outcomes. The retrospective design and the low number of patients may limit the power of the study to detect statistically significant differences. Phase III trials should be stimulated in this context. [Table: see text]
Real-world outcome analysis of EGFR-mutated lung adenocarcinoma with brain metastases.
Authors: Feng-Che Kuan, Wei-Hsun Yang, Hung-Yi Lai, Chun-Chieh Huang, Cheng-Ta Yang, Chung-Sheng Shi
Journal: Journal of Clinical Oncology (2019)

e13588 Background: BM represent a common problem in EGFR-mutated lung adenocarcinoma. The updated Lung-molGPA elucidates the survival in patients with non-small-cell lung cancer and BM by incorporating the effect of EGFR gene alterations. However, the nature history and differences of prognostic implication between common and uncommon EGFR mutations remain unsolved. Methods: By retrospective analysis of Chang-Gung Research Database (CGRD), patients with EGFR-mutated lung adenocarcinoma and BM were included into analysis of PFS and OS. EGFR mutations were categorized into exon 19 deletions (Del19), exon 21 Leu858Arg substitution (L858R) and uncommon mutations. Kaplan-Meier method was used to estimate survival, and multivariate Cox proportional hazard models was performed to estimate adjusted hazard ratios (HR) and 95% confidence interval (CI). The p-value was set to be statistically significant at 0.05 or less. Results: From April 1, 2014 to June 30, 2015, 269 out of 818 patients with EGFR-mutated lung adenocarcinoma and BM were included, of which 115 patients with Del19, 131 patients with L858R, and 23 patients with uncommon EGFR mutations. The baseline characteristics were balanced in age, gender, KPS, ECM, number of BM, and timing of BM. In comparison with those with L858R, uncommon mutations is a poor prognostic factor for PFS (HR 2.24, 95% CI: 1.34-3.75, p = 0.002). The median PFS of Del 19, L858R, and uncommon EGFR mutations were 10.4, 10.0, and 3.2 months, respectively (log-rank p = 0.03). Besides, the median OS of Del 19, L858R, and uncommon EGFR mutations were 18.1, 17.4, and 12.5 months, respectively (log-rank p = 0.05). In comparison with those treated with gefitinib, afatinib treatment is a good prognostic factor for PFS and OS (PFS, HR 0.57, 95% CI: 0.35-0.94, p = 0.03; OS, HR 0.48, 95% CI: 0.26-0.91, p = 0.03). The median PFS of those treated with sequential WBRT, concurrent WBRT and TKI alone were 11.0, 8.5, and 10.3, respectively (log-rank p = 0.63). In addition, the median OS of those treated with sequential WBRT, concurrent WBRT and TKI alone were 18.7, 15.2, and 18.2 months, respectively (log-rank p = 0.50). Conclusions: Among patients with EGFR-mutated adenocarcinoma, common and uncommon EGFR mutations have distinct natural history and prognostic implications in patients with BM.
DNA repair pathway alterations and correlation with immunotherapy response.
Authors: Tatiana Hernandez-Guerrero, Manuel Pedregal, Jaime Rubio, Eva Ruiz-Hispán, Marina Fernandez, Imanol Martinez, Bernard Doger, Yolanda Lage Alfranca, Ana Belen Ruperez, Victor Zenzola, Victoria Casado, Jose Ignacio Martin-Valades, Nerea Carvajal, Cristina Chamizo, Manuel Domine, Jesús García Foncillas, Victor Moreno
Journal: Journal of Clinical Oncology (2019)

e14150 Background: Over the past decade, a better understanding of cancer biology has led to a revolution in immunotherapy. Checkpoint inhibitors (ICI), bispecific antibodies and agonistic agents have shown benefit in cancer treatment. Unfortunately, not all patients benefit and, despite the advances achieved in discovering markers of response, the selection of patients can still be challenging in everyday practice. Methods: We conducted a retrospective analysis of potential prognostic and predictive factors of survival in a cohort of 186 patients enrolled into Phase I Trials testing immunotherapeutic agents at our institution. We computed univariate and multivariate analysis (MVA) of demographics, clinical and molecular characteristics to assess their prognostic and predictive potential of clinical benefit (defined as achieving Complete or Partial Response (CR/PR) as best response or disease stabilization lasting &gt; 120 days) and survival. Molecular testing included Next Generation Sequencing (NGS - Oncomine Comprehensive Assay) grouped in DNA repair, Transcription regulation, Signal Transduction and Cell-Cell interaction pathways. Results: A total of 186 patients (Male/Female: 81/105; median age 61yo) received treatment with either immune checkpoint inhibitors (122 (65,6%)), checkpoint agonists (37 (19.9%)); bispecific antibodies (19 (10.21%) or other immunotherapies (8 (4.29%)) between November 2015 and July 2018. Royal Marsden Score (RMH) was assessed and correlated with progression free survival and overall survival in the total cohort. Median Overall Survival (mOS) was 422 days (CI95%: 345-500 days), 387 (CI95%: 297-478 days), 235 (CI95%: 131-338 days), and 167 (CI95% 64-270 days) for RMH 0, 1, 2 and 3, respectively (p = 0.007). Among 57 patients with NGS results, those with pathogenic mutations in DNA repair pathways (n = 26) showed a trend towards a higher response rate (69% vs 30% p = 0.064) and clinical benefit (65% vs 35%; p = 0.034). Conclusions: Alterations in DNA repair pathways are a potential predictor of benefit of immunotherapy and warrants further studies. A larger cohort of patients is currently being explored in our center to further validate these findings.
A multiplex immunofluorescence assay to assess immune checkpoint inhibitor-targeted CD8 activation and tumor colocalization in FFPE tissues.
Authors: Tony Navas, Kristin Fino, King Leung Fung, Facundo Cutuli, Robert J. Kinders, Aditi Sharma, Geraldine O'Sullivan-Coyne, Alice P. Chen, Toby Tucker Hecht, James H. Doroshow, Ralph E. Parchment
Journal: Journal of Clinical Oncology (2019)

2629 Background: Immune checkpoint inhibitors promote antitumor immune responses by enhancing T-cell activity. Measuring the pharmacodynamic effects of these drugs is challenging, as it requires assessing both immune cell and cancer cell populations. To evaluate T cell activation in tumor tissue from patient biopsies, we developed a robust multiplexed immunofluorescence assay. Methods: Our assay uses novel oligo-conjugated antibodies (Ultivue) for simultaneous quantitation of TCR activation (phospho-CD3zeta), immune checkpoint signaling via PD-1 (p-SHP1/p-SHP2), and the net stimulation/inhibition resulting from the integration of these two pathways in CD8 cells (p-ZAP70), while also providing the proximity of CD8 cells to tumor tissues, identified by β-catenin. The method was clinically validated using custom tissue microarrays (TMA) containing tumor biopsies of 3 different histologies (CRC, NSCLC, and breast). Results: From a total of 192 tumor core biopsies, 20/64 NSCLC, 9/64 CRC, and 3/65 breast TMA cores were found to have a significant number of CD8+ tumor infiltrating lymphocytes (TILs) at baseline ( &gt; 50 cells in the examined section). In 18 of the 20 NSCLC cores, ≥50% of CD8 cells both inside and outside of the tumor were activated (CD3z-pY142+). In 6/9 CRC cores, ≥50% of CD8+ cells inside tumor tissues were activated, and in 4/9 CRC cores, ≥50% of CD8+ cells in stroma were activated. In 2/3 breast tumor cores, 90% of CD8+ cells inside tumor tissues were activated; in the remaining core, 90% of CD8+ cells in stroma were activated. Interestingly, all 192 cores had minimal to no expression of activated Zap70 (pY493) in CD8+ cells. Conclusions: Depending on tumor histology, baseline biopsy samples may contain variable numbers of activated CD8+ TILs (CD3z-pY142+), which may reside inside or outside of tumor regions and express very low levels of Zap70-pY493. Anti-PD-1 therapy is predicted to enhance T-cell cytotoxic activity, as demonstrated by an increased number of TILs and elevated Zap70-pY493 expression. This assay is being used for pharmacodynamic evaluations in ongoing immunotherapy clinical trials. Funded by NCI Contract No HHSN261200800001E.
FRI0337 INCIDENCE AND PREVALENCE OF MYOSITIS ASSESSED BY MULTI-SOURCES CAPTURE-RECAPTURE METHODOLOGY
Authors: alain meyer, Léa Debrut, Lionel Spielmann, Gilles Blaison, Pierre Kieffer, Thierry Martin, Jean Sibilia
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Precise epidemiology of myositis epidemiology remains largely unknown (1). Surveys based solely on administrative claims benefit from large case ascertainment but may be influenced by miscoding and misdiagnosing. The use of medical records with charts review benefit from accurate diagnosis but exhaustive ascertainment is difficult to achieve because numerous specialists are involved and cases may concern both inpatients and outpatients. To overcome these difficulties we undertook a capture–recapture survey that takes advantage of a multi-sources case ascertainment to estimate the number of cases missed by any one source and to correct the prevalence rate (2). <h3>Objectives</h3> To assess the incidence and prevalence of myositis in Alsace, a region of eastern France. <h3>Methods</h3> Alsace, region of eastern France, is home to about 2 million inhabitants benefiting from high access to healthcare and a labialized referral center for myositis. Seeking care outside is uneasy because of peculiar geography. Myositis patients were retrieved through three separate sources: i) all general practitioners and community specialist ii) Muscle pathology center records, iii) all public and private hospitals records, vi) all public and private laboratory records. Incident and prevalent cases fulfilling the ACR/EULAR criteria for myositis were included. <h3>Results</h3> The responses to the questionnaires sent to the physicians (n=3452), yielded 105 potential myositis cases. All hospital centres contacted (n=13) participated in the study and 1335 potential myositis patients were recorded by this source. 263 potential myositis cases were identified through muscle pathology center records. 13 laboratories participate in the studies and 324 potential myositis patients were recorded by this source. We thus received 1863 records of suspected myositis after excluding duplicates within each sources. The thorough review of the corresponding medical charts is currently ongoing and at this stage 10% of the potential cases fulfilled the ACR/EULAR criteria for myositis. <h3>Conclusion</h3> This first study based on a multi-sources capture-recapture methodology and ACR/EULAR criteria is very likely to provide an accurate estimation of myositis epidemiology. <h3>References</h3> [1] Incidence and prevalence of inflammatory myopathies: a systematic review. [2] Meyer A, Meyer N, Schaeffer M, Gottenberg JE, Geny B, Sibilia J. [3] Rheumatology (Oxford). 2015;54:50-63. [4] Brief Report: Spatial Heterogeneity of Systemic Sclerosis in France: High Prevalence in the Northeast Region. [5] Meyer A, Chifflot H, Chatelus E, Kleinmann JF, Ronde-Ousteau C, Klein D, Jégu J, Geny B, Hirshi S, Canuet M, Blaison G, Kieffer P, Lipsker D, Martin T, Sauleau E, Velten M, Sibilia J. Arthritis Rheumatol. 2016;68:1731-7. <h3>Disclosure of Interests</h3> None declared
CALGB 90601 (Alliance): Randomized, double-blind, placebo-controlled phase III trial comparing gemcitabine and cisplatin with bevacizumab or placebo in patients with metastatic urothelial carcinoma.
Authors: Jonathan E. Rosenberg, Karla V. Ballman, Susan Halabi, Colleen Watt, Olwen Mary Hahn, Preston D. Steen, Robert Dreicer, Thomas W. Flaig, Walter Michael Stadler, Christopher Sweeney, Amir Mortazavi, Michael J. Morris
Journal: Journal of Clinical Oncology (2019)

4503 Background: The combination of gemcitabine (G) and cisplatin (C) is a standard therapy for metastatic urothelial carcinoma (mUC). Based on data that angiogenesis plays a role in UC growth and progression, a randomized placebo-controlled trial was performed. Methods: Patients mUC, no prior chemotherapy for metastatic disease and &gt;12 months from prior (neo)adjuvant chemotherapy and ECOG PS 0-1 were randomized 1:1 to G 1000 mg/m 2 IV days 1 and 8 and C IV 70 mg/m 2 day 1 with bevacizumab (GCB) 15 mg/kg IV or placebo (GCP) day 1 every 21 days. Randomization was stratified by the presence of visceral metastases and prior chemotherapy. The primary endpoint was overall survival (OS) defined as the time from randomization to death or last follow-up (FU). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and ≥ grade 3 toxicity. With 445 deaths, the log-rank test had an 87% power to detect a hazard ratio (HR) of 0.74 with a 2-sided α=0.05. The primary analysis was based on the stratified log-rank test adjusting on stratification factors. Alliance Data Safety and Monitoring Board approved the final OS analysis be performed at 420 events due to lower than expected event rates. Results: 506 patients were randomly assigned (252 GCB, 254 GCP) stratified by the presence of visceral disease and prior chemotherapy for UC. The median FU for patients still alive was 46.2 months. Median OS was 14.5 months for patients treated with GCB and 14.3 months for patients treated with GCP with a HR of 0.87 (95%CI 0.72-1.06; 2-sided Wald p=0.17). The HR for PFS was 0.77 (95%CI 0.63-0.93) in favor of GCB (p=0.0074). Grade 3 or greater adverse event rate was 83.5% with GCB compared to 80.7% with GCP. Conclusions: The addition of bevacizumab to GC chemotherapy did not result in improved OS (primary endpoint) in patients with mUC but there was a PFS improvement. The observed median OS of about 14 months is consistent with prior phase III trials of cisplatin-based chemotherapy. Support: U10CA180821, U10CA180882, U10CA180820, U10CA180853, U10CA180888, Genentech https://acknowledgments.alliancefound.org. Clinical trial information: NCT00942331.