tbuckley/cabot-search huggingface dataset:
Product characteristics associated with in vivo expansion of anti-CD19 CAR T cells in patients treated with axicabtagene ciloleucel (axi-cel).
Authors: Frederick Lundry Locke, John Rossi, Sattva Swarup Neelapu, Allen Xue, Marc Better, Xiao Zhang, Armin Ghobadi, Lazaros J. Lekakis, David Bernard Miklos, Caron Alyce Jacobson, Ira Braunschweig, Olalekan O. Oluwole, Tanya Siddiqi, Yi Lin, John Timmerman, Patrick Michael Reagan, Lynn Navale, William Y. Go, Jeffrey S. Wiezorek, Adrian Bot
Journal: Journal of Clinical Oncology (2017)

3023 Background: Axi-cel (formerly KTE-C19) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy. ZUMA-1 is a multicenter, registrational trial of axi-cel in patients (pts) with refractory aggressive non-Hodgkin lymphoma. In a prespecified interim analysis, ZUMA-1 met its primary endpoint, with a 76% objective response rate and a 47% complete response rate ( Blood 2016;128:LBA-6). Post-treatment CAR T cell blood levels were associated with objective response. Here, we describe novel associations between product characteristics and CAR T cell levels in pts. Methods: CAR T cell characteristics in axi-cel produced from 62 pts were analyzed by flow cytometry and modeled against CAR T cell levels. In vivo CAR T cell levels were measured by qPCR. T cell expansion during production (fold expansion/total days in culture) was compared with CAR T cell blood levels, using a partition analysis with expansion rates of ≥1 vs &lt; 1. Wilcoxon 2-sample test and linear regression were used. Results: Axi-cel contained CCR7+ T cells (median, 42%; range, 15–73%), with naïve (CD45RA+/CCR7+; median, 12%; range, 1–57%), central memory (CD45RA−/CCR7+; median, 29%; range, 12–49%) phenotypes, and more differentiated CCR7− effector memory and effector T cells. On infusion, CAR T cells expanded rapidly, reaching peak levels within 2 weeks (median, 43 cells/μL; range, 1–1513), and were also measurable in all pts at 1 month (median, 2 cells/μL; range, 0.03–89). The CCR7+/CCR7− T cell ratio in axi-cel associated positively with peak ( P =0.001) and cumulative ( P =0.003) CAR T cell levels through 1 month. Axi-cel lots that expanded more rapidly during production (≥1.0-fold/d; n = 18/62) associated with higher cumulative levels of CAR T cells ( P =0.03). Other product characteristics, eg, CD4/CD8 ratio or number of infused T cells, were not significantly associated with CAR T cell blood levels. Conclusions: An association was observed between CAR T cell expansion in vivo and both the T cell growth rate during production and product cell phenotype pretreatment. A key attribute of axi-cel product was the presence of CCR7+ naïve/central memory T cells, without upfront T cell subset selection. Clinical trial information: NCT02348216.
Detecting ultra low-frequency variants and gene fusions in lung cancer patients using an amplicon-based Firefly NGS method.
Authors: Li Weng, Lin Wang, Xiao Chen, Jacey Zhang, Chiahui Lin, Yingyu Wang, Tim Brice, Yi Huang, Hongyan Wang, Paul Tang, Zhaohui Johnny Sun, Grace Q. Zhao, Jiatao Lou, Kang Ying, Malek Faham, Shengrong Lin
Journal: Journal of Clinical Oncology (2017)

e23062 Background: The analysis of EGFR, KRAS, and BRAF mutations and Alk fusion is critical for guiding targeted therapy selection, detecting drug resistance, and monitoring residual disease in patients with NSCLC. Designing next-generation sequencing (NGS) assays for detecting low-frequency variants, however, is an ongoing challenge. The limited availability of cfDNA combined with the breadth of coverage necessary to create meaningful, clinically-actionable results requires a solution with multiplex capacity which, in turn, requires greater technological sensitivity and specificity. Here we aim to develop such a solution: an ultra-accurate NGS technology using concatmer-based error correction with amplicon workflow for fast detection of rare mutations including SNV and fusion. Methods: We developed an amplicon-based panel covering variants of EGFR, BRAF, and KRAS, as well as a panel to detect Alk fusion. CfDNA simulate and cfDNA from healthy individuals were used to test assay sensitivity and specificity. Further validation was performed via a comparative analysis of 64 late-stage lung cancer patients using both Firefly -Comet and ddPCR. Results: Analytical sensitivity of the EGFR-TKI 3-gene panel was 100% detection at an allele frequency of 0.1% for 20ng of cfDNA input. Similarly, analytical sensitivity of the Alk fusion panel was 75% detection at an allele frequency of 0.1% and 100% at an allele frequency of 0.25% for the same input. Among our patient cohort, 5 EGFR variants (19del, T790M, L858R, G719X, L861X) and 2 KRAS variant (G12X) were detected. Firefly-Comet demonstrated strong per-variant detection-rate concordance ( &gt; 99%) compared to ddPCR results. The PPV is 100% and the NPV is 98.7%. Statistical analysis of reported allele frequency concordance between Firefly-Comet and ddPCR reveals R-Sq &gt; 0.9. Conclusions: In summary, we have developed Firefly-Comet, an easy-to-use amplicon-based NGS assay capable of detecting single-digit copies of somatic mutants and gene fusions in cfDNA. The multiplex capacity of Firefly-Comet makes it well-suited for supporting targeted therapy selection, drug resistance detection, and treatment monitoring.
Oncological benefit of parenchyma-preserving hepatectomy for colorectal liver metastasis.
Authors: Isamu Hosokawa, Marc Antoine Allard, Hidetoshi Nitta, Real W. Lapointe, Darius Mirza, Gennaro Nuzzo, Eduardo Barroso, Gernot Kaiser, Catherine Hubert, Lorenzo Capussotti, Graeme John Poston, Irinel Popescu, Santiago Lopezben, Jan N.M. IJzermans, Jean-Francois Ouellet, Mauro Salizzoni, Derek Oreilly, Oleg Skipenko, René Adam
Journal: Journal of Clinical Oncology (2016)

3526 Background: Occasionally, major hepatectomy (MH), rather than parenchyma-preserving hepatectomy (PH), is performed for solitary colorectal liver metastasis (CLM). It is unclear whether PH has a disadvantage through increasing liver recurrence or provides an oncological benefit through increasing repeat hepatectomy. The aim of this study was to investigate the prognostic impact of PH vs. MH for solitary CLM. Methods: The study population consisted of a multicentric cohort of 16738 patients operated for CLM between January 2000 and June 2013, and whose data were collected in the LiverMetSurvey registry. Patients with a solitary CLM (≤ 50 mm in size) of the right liver were included in this study. The short- and long-term outcomes of the patients who performed PH (PH group) were compared to those who performed right hepatectomy (MH group). The PH group was matched to the MH group (1:1) by using a propensity score-based method. Results: Of 16738 patients consecutively resected for CLM, 2234 (13%) were eligible for the study, 1800 (11%) underwent PH, and 434 (2%) underwent right hepatectomy. In a matched cohort (PH group, n = 423, MH group, n = 423), PH group was associated with higher rates of liver recurrence (22% vs. 13%; p= 0.001), but PH group was associated with lower rates of extrahepatic disease recurrence (17% vs. 23%; p= 0.05). The 3- and 5-year overall survivals were similar (77% and 60% vs. 70% and 56%, respectively; p= 0.56). In the patients with liver-only recurrence (PH group, n = 284, MH group, n = 40) revealed that, repeat hepatectomy was more frequently performed in the PH group (67% vs. 41%; p= 0.04). The overall survivals at 3- and 5-year were significantly better in the PH group than in the MH group (76% and 60% vs. 65% and 33%, respectively; p= 0.04). Furthermore, the survivals after liver recurrence at 3- and 5-year were significantly better in the PH group than in the MH group (63% and 56% vs. 38% and 31%, respectively; p= 0.04). Conclusions: PH increased liver recurrence but more importantly improved overall survival in patients with liver-only recurrence through increasing repeat hepatectomy.PH should be considered as a standard procedure for solitary CLM.
Promising local control and toxicity profile of systemic therapy with stereotactic body radiation therapy for locally advanced pancreatic cancer.
Authors: Isabel Ruth Preeshagul, Sewit Teckie, Maged Ghaly, Nina Kohn, Craig E. Devoe
Journal: Journal of Clinical Oncology (2016)

e15718 Background: Pancreatic cancer often presents with locally advanced, unresectable disease, for which treatment options include chemotherapy ± local radiotherapy. Stereotactic body radiotherapy (SBRT) allows escalation of radiotherapy dose while minimizing irradiated volume. SBRT achieves considerable local control (LC) in patients with locally advanced disease (LAPC) as well as borderline resectable disease (BRPC). SBRT-related gastrointestinal toxicity presents a challenge for radiotherapy delivery, since the pancreatic head abuts the duodenum. This study evaluates the LC and treatment-related toxicity of an SBRT approach that optimizes pancreatic tumor coverage while limiting duodenal exposure. Methods: A retrospective study analyzing patients with LAPC and BRPC who were treated with SBRT between March 2008 and June 2014. Primary endpoints included local tumor control rate, time to local progression, and locoregional progression free survival. Secondary endpoints include overall survival(OS), gastrointestinal toxicity, and pre/post-treatment abdominal pain. Results: 36 patients underwent SBRT, 25 with LAPC. Median follow up for all patients was 37 months (95% confidence interval (CI): 20 to 87 months). 58% (21/36) received peri-SBRT chemotherapy, 13 were gemcitabine-based. 47% (17/36) received post-SBRT chemotherapy, all gemcitabine-based. 89% of patients received a SBRT dose of 3000cGy delivered over 3 consecutive fractions with strict dose constraints for the duodenum.11 patients were successfully converted to undergo Whipple resection. Early grade 1 and 2 gastrointestinal toxicity developed in 11% of patients; no grade 3 or higher toxicities were identified. Abdominal pain was reported by 42% pre-SBRT and 28% post SBRT. 36% experienced local failure. Median OS was 19 months (95% CI: 13 to 26 months). Conclusions: Our data demonstrate that SBRT can be safely implemented with promising LC and low gastrointestinal toxicity in patients with LAPC and BRPC. 30% of patients were able to undergo successful Whipple resection. Our study supports further evaluation of SBRT as part of the upfront treatment strategy in patients with LAPC/BRPC.
Patient-reported symptoms, unmet needs, and psychosocial outcomes among adult survivors of pediatric and AYA cancer.
Authors: Linda A. Jacobs, Abigail N. Blauch, Donna A. Pucci, Dava Szalda, Steven C Palmer
Journal: Journal of Clinical Oncology (2018)

e22510 Background: Cancer survivors report symptoms that, if unaddressed, may result in unmet needs and difficulties in adaptation. We examined symptoms, unmet needs, and psychosocial outcomes in individuals diagnosed with pediatric (Peds) or adolescent young adult (AYA) cancers. Methods: Peds (n = 123) and AYA (n = 47) survivors presenting in an adult survivorship clinic completed patient-reported outcome measures for 13 symptoms, unmet need for intervention, and symptoms of depression and anxiety (HADS) Results: Participants were 56% female, primarily white (88%), single (60%), and college graduates (77%). Leukemia (35%) and Hodgkin Lymphoma (HL 21%) were the most common cancers, with HL more common among AYAs (p < .001). Most had received chemotherapy (95%) or XRT (60%) and 56% received both. A minority had undergone surgery (31%) or BMT (21%), with surgery more common among Peds (p < .05). 78% of participants reported at least 2 symptoms, while only 33% reported at least 2 unmet needs for intervention. Number of symptoms (M = 6.6, SD = 3.6) and unmet needs (M = 2.2, SD = 2.7) did not differ by diagnostic age, or by endorsement of any given symptom or need (all p > .05). Most common symptoms included anxiety/worry (68%), concentration problems (59%), and memory difficulties (56%) while the most common unmet needs included fatigue (32%), concentration problems (24%), and memory difficulties (23%). Elevated symptoms of anxiety (28%) were common, though symptoms of depression (7%) less so, and neither differed by diagnostic age group (p < .05). A minority of those with elevated anxiety (44%) or depressive symptoms (42%) reported an unmet need for intervention for these difficulties. Number of symptoms and unmet needs were associated with anxiety (both r > 0.39) and depression (both r > 0.39; all p < .001). Conclusions: Patient-reported symptoms are common among adult Peds and AYA cancer survivors, while unmet needs are less prevalent. Neither differs by age at diagnosis. Symptoms and unmet needs, however, may reflect anxiety and depressive symptoms for which survivors may be more willing to accept intervention than for emotional difficulties per se, representing an opportunity for intervention to improve outcomes.
Audit study of cancer research mentorship opportunities by NCI-funded PIs: Analysis of a pathway barrier for diversity.
Authors: Jeffrey D. Robinson, Nathan Dieckmann, Elizabeth Withers, Dena Hassouneh, Charles R. Thomas
Journal: Journal of Clinical Oncology (2017)

6566 Background: The pipeline of diverse cancer researchers is critical. Audit studies suggest that racial discrimination disadvantages black (vs. white) people with respect to educational/professional advancement (Milkman, 2012). We hypothesized that prospective Black (B) male doctoral students would experience greater disparity in responses when seeking access to NCI-funded PIs compared to prospective Caucasian (W) males. Primary aim: To explore response and acceptance rates for B (vs. W) men seeking cancer-research mentorship. We also explore similar differences when considering evaluators’ race and sex. Methods: Between 9-9:30 am (local time) during a Monday in Oct 2015, identical emails were sent to 1028 randomly selected PIs affiliated with 65 NCI-designated cancer centers. PIs were randomly assigned to receive emails from either ‘Brad Anderson’ (W; n = 513) or ‘Lamar Washington’ (B; n = 515). Primary outcomes: (1) any response within one week (yes/no); and (2) type of response if received (agree to meet/not agree to meet). Logistic regression was used to examine unadjusted and adjusted effects of condition (W/B) on the primary outcomes. In adjusted models, PI sex and time zone were included as covariates (PIs identified as African American = 1.2%). Results: Approximately 50.0% and 48.3% of the sample responded to ‘Brad’ and ‘Lamar,’ respectively. Condition was not a significant predictor of ‘any response’ in either unadjusted (p = .62, odds ratio 95% CI = 0.83-1.35) or adjusted (p = .62, odds ratio 95% CI = 0.83-1.36) models. In the adjusted model, neither PI sex nor time zone were significant predictors of ‘any response.’ For those who responded, 43.7% and 40.9% ‘agreed’ to meet with Brad and Lamar, respectively. Condition was not a significant predictor of ‘response type’ in either unadjusted (p = .53, odds ratio 95% CI = 0.78-1.61) or adjusted (p = .51, odds ratio 95% CI = 0.78-1.64) models. In the adjusted model, only PI sex was a significant predictor of ‘response type’ (p = .03, odds ratio 95% CI = 1.04-2.29), with males (45.8%) being more likely to ‘agree to meet' than female PIs (35.6%). Conclusions: We did not find strong evidence of bias by NCI-funded PIs against B (vs. W) prospective Ph.D. students.
Phase II study of carboplatin and pemetrexed followed by gefitinib for patients with advanced non-small cell lung cancer harboring sensitive EGFR mutation.
Authors: Saki Manabe, Fumihiro Oshita, Shuji Murakami, Tetsuro Kondo, Haruhiro Saito, Takeshi Kaneko, Kouzo Yamada
Journal: Journal of Clinical Oncology (2016)

e20581 Background: To evaluate the efficacy, safety and survival of carboplatin and pemetrexed (Cb/Pem) as induction therapy followed by gefitinib (Gef) maintenance in patients with EGFR-positive advanced non-small cell lung cancer (NSCLC). Methods: Eligible patients received 4 courses of Cb (AUC 6 mg/mL∙min) /Pem (500 mg/m2), followed by sequential Gef (250 mg once daily). The primary endpoint was the 2-year survival rate. Secondary endpoints were progression-free survival (PFS), overall survival (OS), tumor responses, and the rate of adverse events. Based on an expected rate of 60% and a threshold rate of 40% at 2 years, 54 cases were required with α < 0.1 and β < 0.1. This study was to be effective if 28/54 patients survived for > 2 years. If fewer than 12 of the first 29 patients survived beyond 2 years then the trial was to be stopped. Results: 29 patients were enrolled between June 2010 - January 2015 and we performed an interim analysis The median age was 64 years, 27 patients had stage IV, and 2 patients were postoperative recurrence. There were 6 males and 23 females, performance status was 0 and 1 in 17 and 12 patients, and EGFR gene variations were Ex18, Ex19, and Ex21 in 1, 14, and 14 patients. 1 patient wasn't met starting criteria; therefore, 28 patients were analyzed. The median follow-up time was 30.2 months (range 7–65). 16 patients (57.1%) had partial response for Cb/Pem therapy and all of the patients were switched to Gef. The reasons for switching Gef were completion of Cb/Pem in 21 patients, toxicity in 5 patients, and the doctor’s judgment in 2 patients. There were no febrile neutropenia or treatment-related deaths. The overall response rate was 85.2%. The 2-year survival rate was 62.9%, PFS was 16.0 months and OS was not met. According to the EGFR gene variants, the PFS was 17.0 and 15.0 months for patients with Ex19 and Ex21. The OS was not met for patients with Ex19 and was 26.0 months for patients with Ex21. Conclusions: Cb and Pem followed by Gef maintenance therapy might be an initial treatment option for advanced EGFR-positive NSCLC patients. This study was decided to stop after the first stage of enrollment because of the slow enrollment and a phase III study had been started. Clinical trial information: UMIN000003354.
Exaggeration of median progression-free survival (PFS) by blinded, independent, central review (BICR).
Authors: Andrew Stone, Val Gebski, Richard Davidson, Ralph Bloomfield, Jonathan Bartlett, Antony Sabin
Journal: Journal of Clinical Oncology (2018)

e14522 Background: Recent published studies have shown large discrepancies between locally evaluated (LE) median PFS times and those assessed by BICR. We show that, in many cases, this can be attributed to deficiencies in standard methodology rather than bias. When only local review shows progression, no further assessments are performed and patients (pts) are censored in the BICR analysis. It is likely that a positive correlation exists between BICR and LE PFS times, so this type of censoring is informative and violates the assumptions used in the construction of Kaplan–Meier (KM) curves. Generally, this informative censoring does not result in meaningful bias in the estimation of the hazard ratio (HR). Methods: A simulation study of 200 pts was performed to assess the impact on median PFS estimated by BICR, varying the correlation between BICR and LE (0.2–0.9). It was assumed that the true BICR and LE medians were equal (19 or 6 months [m]) and that pts were scanned every 12 weeks. In addition, a case study from three maintenance trials of PARP inhibitors in platinum-sensitive BRCA-mutated ovarian cancer was assessed. Results: KM estimates of BICR medians were exaggerated by 1–9 m on average when the true median was 19 m and by < 1.5 m when the true median was 6 m. The extent of bias increased when pts were scanned more often. These findings were corroborated in the case-study trials. Conclusions: These findings show that BICR medians will be exaggerated if there is a positive correlation between BICR and LE PFS times, especially when pts are assessed many times prior to progression. When efficacy is substantial, this can lead to exaggeration of the difference in medians between arms. Trials in the same indication should therefore consistently report both LE and BICR results. Further research is needed to identify alternative approaches to estimating the survival curve with informative censoring. BRCA-mutated subset n LE BICR Median (m) HR (95% CI) Median (m) HR (95% CI) SOLO2, olaparib NCT01874353 295 19.1 vs 5.5 0.30 (0.22, 0.41) 30.2 vs 5.5 0.25 (0.18, 0.35) NOVA, niraparib NCT01847274 203 14.8 vs 5.5 0.27 (0.18, 0.40) 21.0 vs 5.5 0.27 (0.17, 0.41) ARIEL3, rucaparib NCT01968213 196 16.6 vs 5.4 0.23 (0.16, 0.34) 26.8 vs 5.4 0.20 (0.13, 0.32)
Predictive impact of different exon 19 deletions in EGFR-mutant NSCLC treated with first-line TKIs.
Authors: Sabrina Rossi, Luca Toschi, Giovanna Finocchiaro, Ettore D'Argento, Vincenzo Pio Di Noia, Alessandra Cassano, Maria Bonomi, Eleonora Cerchiaro, Giovanni Luca Ceresoli, Giordano D. Beretta, Carlo Barone, Armando Santoro
Journal: Journal of Clinical Oncology (2017)

e20608 Background: Common Epidermal Growth Factor Receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) predict sensitivity to EGFR tyrosine-kinase inhibitors (TKIs), with exon 19 deletions being associated with better outcome when compared to L858R mutations. We aimed to investigate the impact of different exon 19 deletions on patient outcome in EGFR-mutant NSCLC treated with first-line TKIs. Methods: In this retrospective analysis we included 98 patients with metastatic NSCLC and EGFR exon 19 deletions, treated with first-line EGFR TKIs (gefitinib or afatinib) in 3 Italian centers between 2011 and 2016. The primary endpoint was overall survival (OS), the secondary endpoint progression free survival (PFS). Analyses were performed by grouping exon 19 deletions according to two different models: type of deletion (delE746-A750 vs other) and starting codon of deletion (E746 vs L747). Kaplan-Meier method, the log-rank test and multivariate Cox regression models were used to estimate survival outcomes. Median follow-up time was 40 months. Results: All groups resulted well balanced in terms of patients’ characteristics but the percentage of patients treated with gefitinib was significantly superior in E746 group compared to L747 (p = 0.02). In the whole cohort median OS was 24.6 months [95%CI 21.9 – 33.1] while median PFS was 13.7 months [95%CI 11.6 – 15.9]. When delE746-A750 (n = 60) was compared to the other deletions in exon 19 (n = 38), no differences were evidenced either in terms of OS (24.1 vs 26.0 months; HR 0.80 [95%CI 0.5 – 1.4]; p = 0.42) or PFS (13.9 vs. 12.8 months; HR 0.99 [95%CI 0.6 – 1.6]; p = 0.97). Similarly, no difference in OS or PFS emerged comparing E746 (n = 73) versus L747 group (n = 25) (OS:24.6 and 26.0 months, respectively, HR 0.79 [95%CI 0.4 – 1.4; p = 0.45; PFS 13.9 vs 12.9 months, respectively (HR 0.87 [95%CI 0.5 – 1.4] p = 0.57). On multivariate analysis including age, sex, smoking history, deletions (delE746-A750 vs others or E746 vs L747), presence of brain metastases at diagnosis or during TKI treatment, no variable resulted associated with longer OS or PFS. Conclusions: Different exon 19 deletions are equally sensitive to first-line EGFR TKIs in EGFR-mutant NSCLC.