tbuckley/cabot-search huggingface dataset:
Long-term survival of adjuvant high-dose (HDC) vs weekly cisplatin (WC) for human papilloma-virus (HPV) and non-HPV head and neck squamous cell carcinoma (HNSCC).
Authors: Katharine Andress Rowe Price, Ashish V. Chintakuntlawar, Robert Leonard Foote, Yolanda I. Garces, Daniel Ma, Michelle A. Neben-Wittich, Eric J. Moore, Jan C. Kasperbauer, Daniel L. Price, Jeffrey R. Janus, Kathryn M. Van Abel, Jessica Lyn Geiger
Journal: Journal of Clinical Oncology (2019)

6071 Background: Phase III data suggests a benefit of HDC in the adjuvant setting, but the effect of HDC and WC on long term survival and for HPV+ HNSCC is unknown. Methods: Data from a published retrospective study (Geiger Oral Onc 2013) of HDC vs WC in resected HNSCC was updated. Overall survival (OS) and recurrence-free survival (RFS) was assessed by Kaplan-Meier method for all pts and by HPV status. Multivariate analyses were performed to assess impact of HPV status, smoking, age, HDC vs WC, and cumulative cisplatin dose ( &lt; 200mg/m 2 vs ≥200 mg/m 2 ). Results: 51 patients (pts) received HDC and 53 WC. Median follow-up was 8.7 yrs (0.8-13.7). For the whole cohort, HDC had significantly improved OS over WC (p = 0.0095; 5- and 10-yr OS 84% and 80% vs 72% and 60%). No OS benefit for HDC was seen in pts with HPV+HNSCC (5- and 10-yr OS 90% and 87% for HDC and 81% and 81% for WC; p = 0.51). For HPV-negative HNSCC, OS had borderline significance with HDC vs WC (5- and 10-yr OS 73% and 68% vs 65% and 44%; p = 0.06). For the whole cohort, there was no difference in 5- and 10-yr RFS (78% and 74% for HDC vs 72% and 62% for WC; p = 0.32). When analyzed by HPV status, there was no difference in RFS with HDC or WC for either HPV+ (p = 0.43) or HPV-negative HNSCC (p = 0.97). On multivariate analyses of OS for all pts, only HPV status was significant (p = 0.0011; HR 0.27, CI 0.12-0.62). For HPV+ HNSCC, there was no significant predictor of OS. For non-HPV HNSCC, the benefit of HDC approached significance with a decreased risk of death (HR 0.38; p = 0.07). For all pts, those who received ≥200mg/m 2 had significantly improved OS (5-yr 90% vs 72% and 10-yr 86% vs 61%; p = 0.004). By HPV status, cumulative dose had no significant effect on OS. Conclusions: OS is better with HDC and with cumulative dose &gt; 200 mg/m 2 in unselected patients. The benefit of cisplatin is likely higher for non-HPV HNSCC. A difference in OS with no difference in RFS suggests non cancer-related causes of death in the WC cohort. Ability to receive HDC could be a surrogate marker of comorbidity. [Table: see text]
Notch family gene mutations associate with high tumor mutational burden in diverse cancers.
Authors: Da Jiang, Zhaojian Niu, Jianli Zhang, Yanlei Wang, Liang Shang, Bixun Li, Jun Guo, Baogui Wang, LingQin Zhao, Wenjing Wang, Qiang Cui, Xiaodong Pan, Jinwei Hu, Shiyue Zhang, Kai Wang
Journal: Journal of Clinical Oncology (2019)

e14616 Background: The Notch pathway has an important role in tumorigenesis in many types of cancer. Clinical trials with Notch inhibitors are ongoing. Recently, Notch pathway has been reported to be part of tumor immunity and patients with NOTCH1 mutations (mut) showed better outcome to PD-1 inhibitors, however, the underlying mechanism is unknown. Methods: Next generation sequencing (NGS) panel of 450 cancer genes was performed on FFPE tissue and matched blood samples from 1341 solid tumors, including hepatocellular carcinoma (HCC, n = 644), esophageal carcinoma (EC, n = 255), breast cancer (BC, n = 175), small cell lung cancer (SCLC, n = 141), head and neck cancer (HNC, n = 77). Notch family gene (NOTCH1/2/3/4) muts were analyzed. Genomic alterations including single base substitution, short and long insertions/deletion, copy number variation, gene fusion and rearrangement were assessed. Tumor mutational burden (TMB) was calculated in all patients by NGS algorithms. TMB high (TMB-H) was defined as TMB values ≥75% tumors in each tumor type. Results: For all patients, Notch family gene mut (substitution/indel/truncation) were found in 27% EC, 19% SCLC, 12% HNC, 6% BC and 5% HCC. The median TMB was 6.1 muts/Mb. In general, tumors with Notch family gene mut had significantly higher median TMB in pan-cancer cohort when compared with tumors without Notch family gene mut (9.2 vs. 6.1 muts/Mb, p &lt; 0.001). Specifically, tumors with NOTCH1 mut had higher TMB in HCC (8.5 vs 5.5, p = 0.034), in BC (23.2 vs. 4.6, p = 0.006) and in SCLC (14.0 vs. 9.4, p = 0.002), while NOTCH2 mutant tumors presented higher TMB in HCC (18.5 vs. 5.5, p = 0.026), in EC (14.7 vs. 6.9, p = 0.001) and in SCLC (13.2 vs. 4.6, p = 0.026). We found 65% of NOTCH1 mut were located in epidermal growth factor (EGF)-like repeats domain. Classes of the NOTCH1 mutation type were substitution/indel (non-frameshift) (58%) and truncation (42%), while NOTCH2 mut were 88% and 12%. In TMB-H tumors, substitution/indel is the predominant mutation type of Notch family gene (NOTCH1 61%, NOTCH2 100%). Conclusions: Tumors with Notch family gene mut presented higher TMB in multiple cancer types, indicating a potential strategy for targeted and immunotherapy in NOTCH mutant cancers.
A phase II, open label, multicenter trial of avelumab in patients with advanced, metastatic high-grade neuroendocrine carcinomas NEC G3 (WHO 2010) progressive after first-line chemotherapy (AVENEC).
Authors: Christian Fottner, Leonidas Apostolidis, Martina Ferrata, Sebastian Krug, Patrick Michl, Arno Schad, Wilfried Roth, Dirk Jaeger, Peter R. Galle, Matthias M. Weber
Journal: Journal of Clinical Oncology (2019)

4103 Background: High grade Neuroendocrine Neoplasias (NEN) are rare tumors with a poor prognosis and no established second line therapy when progressive after first line platinum-based chemotherapy resulting in a median overall survival (OS) of 5 months. This study aims to evaluate the efficacy and safety of the anti-programmed death ligand-1 (PD-L1) antibody Avelumab in patients (pts) with NEN G3 progressing after first-line chemotherapy. Methods: In a multicenter, national, single-arm, open-label, phase II trial the efficacy and safety of Avelumab was evaluated in patients with metastatic progressive Neuroendocrine Carcinomas (NEC G3) according to WHO 2010, excluding Merkel cell carcinoma and small cell lung cancer. Results: From 12/2017-11/2018 a total of 29 pts (20 male, 69%), were enrolled (16 NEC G3 and 11 moderately differentiated NETG3). Mean age was 59.2±10.2 ys (range 33-75), median follow up 16.5 weeks (3-48). Median Ki67 was 60% (range 20-95%). Site of origin included pancreas (12), genito-urinary tract (4), stomach-esophagus (3), colo-rectum (3), lung (2), ear-nose-throat (2), papilla of Vater (1). In an interim analysis the DCR (stable disease or partial remission according to irRECIST) after 8 weeks was 32% (4 SD, 2 PR). In responders, mean duration of disease control was 20 (±13.8) weeks, with 4 pts. showing stable disease or partial remission ≥6 months. Median OS was 4.2 months (range 1- &gt;12). Treatment-related adverse events occurred in 11 of 29 pts (38%) and were mainly mild to moderate (CTCAE-grade 1 [52%], 2 [44%] and 3 [4%]) and included fatigue (n=6; 20.6%), diarrhea (n=4; 13.7%), fever/chills after infusion (n=4; 13.7%), loss of appetite and nausea (n=4; 13.7%), skin rash (n=1; 3%), deterioration of preexisting psoriasis (n=1; 3%) and abdominal pain (n=1; 3%). Conclusions: Immune checkpoint blockade with avelumab in pretreated high grade NEN shows relevant activity in a subset of patients with excellent tolerability. Clinical trial information: NCT03352934.
The relative impact of patient and institutional rurality on lung cancer disparities.
Authors: Meredith Ray, Nicholas Ryan Faris, Anna Derrick, Matthew Smeltzer, Raymond U. Osarogiagbon
Journal: Journal of Clinical Oncology (2019)

e20052 Background: We quantified variation in stage specific, guideline concordant treatment and examined the interaction with rurality and overall survival (OS). Methods: We used tumor registry data for non-small cell lung cancer (NSCLC) patients at 5 institutions in the Mississippi Delta from 2011-2017, including patient demographics, clinical stage, treatment, and OS. We defined rurality by Rural-Urban Commuting Area codes, hospital and patient zip codes; based stage-stratified treatment on National Comprehensive Cancer Network guidelines; used Chi-squared and ANOVA F-tests to assess differences across institutions and logistic regression to assess associations between appropriate care, patient- and institution-level rurality. We used Log-rank tests to examine differences in OS and Cox proportional hazard regression to calculate hazard ratios (HR). Results: 6,259 patients were identified across 2 rural (n = 1255, 20%) and 3 metropolitan (metro) institutions (n = 5004, 80%). There were significant demographic and clinical differences between institutions: proportion of African-Americans (range: 6-37%, p &lt; 0.001), uninsured (3-18%, p &lt; 0.001), patient rurality (17-99%, p &lt; 0.001), ‘no treatment’ rates (17-31%, p &lt; 0.001). Metro patients or those treated at metro institutions were more likely to receive guideline-concordant treatment (odds ratio: 1.34, 95% CI [1.20 - 1.49]; 1.45 [1.28 - 1.65], respectively) than their rural counterparts and had improved OS (HR: 0.89; 95% CI [0.84 - 0.95]; 0.68 [0.63 - 0.72], respectively). They were also less likely to receive ‘no treatment’ (0.62 [0.55 - 0.71], p &lt; 0.001; 0.51 [0.49 - 0.66], p &lt; 0.001, respectively). Among patients with proper care, there were no patient-level rurality based OS differences (p = 0.2203) but those treated at metro institutions had better OS (p &lt; 0.001). When stage-stratified, only advanced-stage patients treated at metro institutions had better survival (p &lt; 0.001), no other differences in OS were detected for early or late-stage patients. Conclusions: Institution-level rurality had greater influence than patient-level rurality on receipt of guideline concordant care and OS. Appropriate care eliminated patient-level rurality OS disparities.
Metastatic pattern and tumor sidedness in colorectal cancer.
Authors: Mahvish Muzaffar, Abdul Rafeh Naqash, Darla K. Liles, Sumyra Kachru
Journal: Journal of Clinical Oncology (2019)

e15147 Background: Tumor side has emerged as an important prognostic and predictive factor in metastatic colon cancer. We sought to study its impact on the metastatic pattern of colorectal cancer. Methods: The SEER database (version 8.3.5) was reviewed for patients with Stage IV colorectal cancer diagnosed between 2004-2015. We only included patients with labeled primary site, and excluded appendiceal, unlabeled and autopsy alone cases. Variables included in the analysis were: age, race, gender, grade, primary tumor side and sites of metastasis at diagnosis. Primary outcome analyzed was overall survival and disease specific survival.Cox proportional hazard regression model was employed to test the association between survival and side of cancer/ site of metastasis. Results: A total of 74,768 cases were identified who met the eligibility criteria. The mean age was 68.5 yrs. for right colon cancer (RCC),64.0 yrs. for left colon cancer (LCC). and 62.9 yrs. for rectal cancer. White race was predominant group for RCC, LCC and rectum. More females were vs men in RCC (52% vs 48%), LCC (44% vs 56%) and rectum (60% vs 40%). (The cox regression model suggested inferior outcome for black race HR 1.05(1.03-1.07) (&lt;0.001), high grade HR 1.32(1.30-1.35) p&lt;.0001, right side tumors HR 1.23(1.21-1.250, p &lt;.0001 (table). Conclusions: Over last few years tumor sidedness has emerged as an important prognostic and predictive factor in colon cancer. Our study also highlights the impact of sidedness on survival irrespective of distant metastatic pattern. This analysis contributes to the ongoing discussion that right and left colon cancer are two distinct disease entities. Impact of primary tumor side and metastatic site on survival in colorectal cancer. [Table: see text]
Hyperprogressive disease in patients with recurrent high grade gliomas treated with immune checkpoint inhibitors or other therapies.
Authors: Laura Donovan, Samuel Gedailovich, Adela Joanta-Gomez, Jessica Schulte, Teri Nguyen Kreisl, Andrew B. Lassman, Mary Roberta Welch, Aya Haggiagi, Fabio Massaiti Iwamoto
Journal: Journal of Clinical Oncology (2019)

e13575 Background: Hyperprogressive disease (HPD) has been described in solid tumor patients treated with immune checkpoint inhibitors (ICI). HPD is defined as a ≥2-fold increase in tumor growth rate (TGR) following initiation of ICI. HPD has not been explored in patients with high grade gliomas (HGG) on ICI or standard cytotoxic regimens. In advanced cancer patients receiving ICI, MDM2/4 amplification or EGFR alterations, both found in HGG, correlated with HPD. We compared the rate of HPD in recurrent HGG patients receiving ICIs to those treated with non-immunotherapy agents. Methods: Patients with HGG on ICIs for 1st or 2nd recurrence were compared to a control group receiving other therapies at 1st recurrence. Patients with prior or concurrent bevacizumab or anti-VEGFR were excluded due to pseudoresponse and decreased enhancement with these drugs. HPD was calculated by comparing TGR immediately before and after treatment. Results: 49 patients met inclusion criteria (27 ICI, 25 control). 25/27 patients treated with ICIs and 20/22 patients in the control group had complete imaging and were eligible for analysis. In the ICI group, 60% were men (15/25) and 88% (22/25) had a diagnosis of GBM. 68% were treated at first progression (17/25). Controls were 80% male (16/20) and all had a diagnosis of GBM. 30% (6/20) were 65 years or older at diagnosis in the control group compared to 28% (7/25) in the ICI group. In total, 7/25 patients met criteria for HPD in the ICI group (28%) compared to 4/20 patients in the control group (20%). 10/25 patients (5/7 with HPD) in the ICI group and 8/20 patients (2/4 with HPD) in the control group had next generation sequencing of their tumors. EGFR alterations and MDM2/4 amplifications were not associated with HPD whereas PTEN mutations were more common in the HPD group (71% HPD vs. 33.3% no HPD). Conclusions: HPD is observed in patients with HGG treated with ICI at comparable rates to those with other cancers, but was also observed in 20% of patients receiving other therapies. While the numbers are small, PTEN mutations may be associated with HPD in patients with HGG. In contrast to other solid tumors, EGFR alterations and MDM2/4 amplifications were not associated with HPD in HGG.
Radium 223 (Ra-223) experience in twenty-four castration resistant prostate cancer (CRPC) patients treated at West Virginia University (WVU) 2014-2018.
Authors: Zeeshan Ahmad, Ruta Arays, Kenneth Veselicky, Joanna Amy Kolodney, Thomas F. Hogan
Journal: Journal of Clinical Oncology (2019)

e16502 Background: Ra-223 was FDA approved for CRPC with symptomatic bone metastases without visceral metastatic disease. Methods: De-identified IRB exempted records were abstracted for demographic, clinical, and laboratory data from CRPC men treated with Ra-223 at WVU 2014-2018. Results: 24 men had in total 95 Ra-223 infusions; 20 men (83%) were referred from outside institutions. Average ages (yrs; ranges) were 63 (48-87) at initial PC diagnosis; 68 (49-89) at first WVU-visit; and 69 (54-89) at first Ra-223 infusion. At diagnosis, 4 men (17%) had prostatectomy; 12 (50%) were M1/stage 4; PSAs ranged from 7-9,600 ng/mL. In 24 men, there were 73 courses of different androgen deprivation therapies (ADT); all had one, 22 (92%) two, 17 (71%) three, &amp; 10 (42%) four or more; 68 (93%) of the 73 ADT trials preceded Ra-223. In 24 men, 19 (79%) had docetaxel or cabazitaxel chemoRx; 10 of 19 (53%) had 2 nd line and 2 of 19 (11%) had 3 rd - 4 th line; chemoRx preceded Ra-223 in 18 of the 19 men (95%). In 24 men, 19 (79%) received 33 courses of radiation; in 9 of 33 (27%) the prostate was targeted; another 24 (73%) were palliative; 18 of 19 men (95%) had radiation before Ra-223. In 24 men, 24 had a 1 st Ra-223 infusion, 21 (88%) a 2 nd , 16 (67%) a 3 rd , 12 (50%) a 4 th , 12 (50%) a 5 th , and 10 (42%) a 6 th infusion; 14 men (58%) did not complete 6 infusions, most stopping for clinical decline or death. In 24 men, median overall survival (OS) from first Ra-223 infusion to last visit or death was 4.9 months (0-33); OS from last Ra-223 infusion was 1.2 months (0-28); 13 men (54%) remain alive &amp; 3 (13%) continue Ra-223. Conclusions: Our CRPC patients’ best OS of 4.9 months with Ra-223 does not match the 14.9 months first reported (NEJM 2013; 369:213-223). Fourteen of our 24 men (58%) did not complete 6 planned Ra-223 infusions because of clinical decline or death. This may represent a “real world referral bias” of heavily pre-treated patients as documented above. Selecting more appropriate patients for Ra-223 is currently under review (https://www.esmo.org/Oncology-News/EMA-PRAC-Recommends-Restricting-Use-of-Prostate-Cancer-Medicine-Radium-223-Dichloride)
Impact of tumor shrinkage pattern by biweekly triplet gemcitabine/cisplatin/s-1 for biliary tract cancers: Implication for neoadjuvant therapy (KHBO1401-1A study).
Authors: Shogo Kobayashi, Hidetoshi Eguchi, Masashi Kanai, Hiroshi Wada, Daisuke Sakai, Hideo Baba, Satoru Seo, Akinobu Taketomi, Kenichi Yoshimura, Etsuro Hatano, Hiroaki Nagano, Tatsuya Ioka
Journal: Journal of Clinical Oncology (2019)

4093 Background: There have not been any new evidenced regimen for biliary tract cancers (BTC) after ABC-02 study, we conducted biweekly triplet gemcitabine/cisplatin/s-1 regimen (GCS) and compared with conventional doublet gemcitabine/cisplatin regimen (GC) as phase III (KHBO1401) study. Biweekly GCS was proved not only to prolong patients’ survival (HR 0.791 (90% C.I. 0.628-0.996), one-sided P = 0.046) but also to achieve high response rate (42% versus 15%, P &lt; 0.001) and good conversion rate (2.5% versus 0.0%), and would be good for neoadjuvant therapy. Herein, we investigated tumor shrinkage pattern to explore possibilities of neoadjuvant therapy. Methods: Totally 246 patients were enrolled in multi-center phase III KHBO1401 study between 2014 and 2016. Tumor shrinkage pattern (best response, timing, response at 100 days (14 weeks, approx. 6 cycles in GCS and 4 cycles in GC), etc.) and survival were investigated in the patients with measurable BTC (n = 183, 74%, 91 in GCS and 92 in GC) as sub-analysis. P &lt; 0.05 was considered statistically significant. Results: Tumor shrinkage pattern could be divided to 4 categories by the response at 100 days after enrollment; category A ( &lt; -30% in size), B (-30% to 0%), C (0% to +20%), and D ( &gt; +20%). GCS arm contained more category A &amp; B (61 (67%) vs. 33 (36%), P &lt; 0.0001). Each category predicted best response and overall survival (p &lt; 0.0001). Timing for maximum tumor response were different among categories, category A achieved maximum tumor shrinkage at 165 +/- 76 days in GCS and 225 +/- 190 days in GC, category B at 139 +/- 78 versus 154 +/- 82 days, and category C and D did not achieve tumor shrinkage. Maximum tumor shrinkage in category A was -53% in GCS versus -65% in GC (P = 0.0892), and 20% patients in GCS underwent tumor regrowth 154 +/- 143 days later. Conclusions: GCS provided faster and more tumor shrinkage with better survival in the comparison of GC, although it had 20% risk of re-growth after 6 cycles.
Predictive factors of cytoreductive surgery in epithelial ovarian cancer in a Mexican women cohort.
Authors: Flavia Morales Vasquez, Ricardo Raziel Peña Gonzalez, Horacio Noé López Basave
Journal: Journal of Clinical Oncology (2019)

e17099 Background: Cytoreductive surgery is the most important prognostic factor in ovarian cancer. To identify in a timely manner the patients who are not candidates for optimal debulking, does not delay and optimize the treatment. Objetive: Identify the presurgical factors that characterize patients in whom optimal cytoreduction is not possible. Methods: Observational study in a retrospective cohort (n = 255) that compared pre-surgical factors between patients with optimal debulking (n = 65) and suboptimal (n = 190). Non-parametric tests were used, a Cox proportional hazards model was constructed and survival curves were drawn by method of Kaplan y Meier. Results: 255 patients were included. 75% achieved optimal debulking. 9 out of 10 evaluated tomography criteria showed association (p &lt; 0.001) with suboptimal cytoreduction. The best cut-off value of Ca-125 to predict suboptimal surgery was 774 IU / mL. Only clinical ascites showed association with the result of the surgery (p &lt; 0.001). There was no difference in complications between both groups (p = 0.267). The rate of optimal debulking has improved over time (p = 0.049). The turn of the surgeries has no impact on the overall survival of the patients (p = 0.792). Conclusions: Objective parameters (tomography and laboratory) should be used to select patients who are not candidates for surgery. The Clinical evaluation without objective parameters is not enough
Phase II study of a telomerase-specific oncolytic adenovirus (OBP-301, Telomelysin) in combination with pembrolizumab in gastric and gastroesophageal junction adenocarcinoma.
Authors: Uqba Khan, Talia Biran, Allyson J. Ocean, Elizabeta C. Popa, Joseph T. Ruggiero, Doru Paul, Chelsea Garcia, David Carr-Locke, Reem Sharaiha, Yasuo Urata, Manish A. Shah
Journal: Journal of Clinical Oncology (2019)

TPS4145 Background: Although checkpoint inhibitors (CPIs) can produce durable responses in gastric cancer patients (pts) in the 3rd line setting, the response rate is only 10-15%. Therefore, there is a huge unmet need to enhance the response rate of CPIs to provide benefit to wide range of pts. A novel concept in immuno-oncology is the use of cancer specific oncolytic viral therapy. In addition to the specific killing of the tumor by the virus, these agents can induce an immunogenic cell death in the tumor to augment the immune activation driven by PD-1 inhibition. OBP-301 is an oncolytic adenovirus genetically modified to be able to selectively replicate in cancer cells by introducing human telomerase reverse transcriptase (hTERT) promoter. Results of a phase I study of OBP-301 in solid tumor pts demonstrated the safety and efficacy of intra-tumoral injection of OBP-301. A pre-clinical study of the combination of OBP-301 with anti-PD-1 antibody has also shown significant synergistic activity as well. Based on these encouraging pre-clinical and clinical data, we designed a phase II clinical trial to examine the safety and efficacy of combination of pembrolizumab and OBP-301 in the treatment of PD-L1 positive metastatic gastric/GEJ adenocarcinoma. Methods: This is a multicenter, non-randomized phase II trial of OBP-301 with pembrolizumab in metastatic gastric/GEJ adenocarcinoma that has progressed on at least 2 lines of prior therapy. Eligibility criteria include PD-L1 positive tumors as defined by a combined positive score, performance status ≤1, and good end organ function. The primary endpoints are to examine objective response rate and safety of OBP-301 with pembrolizumab. The secondary endpoints are to examine disease control rate, duration of response, overall survival and progression free survival. Correlative studies are planned to identify biomarkers for response to combination therapy by using multiparameter flowcytometry, single-cell transcriptional profiling and immunohistochemistry. All eligible pts will receive 1x10 12 Viral Particles/mL of OBP-301 administered every 2 weeks for total of 4 injections, injected directly into tumor via upper endoscopy. Every pt will also receive pembrolizumab 200 mg IV every 3 weeks for 2 years or until progression. Pts will be enrolled in a Simon two stage design, with 18 pts in the first stage. If 3 or more pts respond to the combination therapy, the study will move forward to stage 2, with 19 more pts enrolled. The study is currently enrolling pts.