tbuckley/cabot-search huggingface dataset:
Triple combination treatment with anti-EGFR monoclonal antibody, low-dose chemotherapy, and anti-PD1 immune check-point inhibitors for recurrent and/or metastatic head and neck squamous cell carcinoma: A single institute experience.
Authors: Ying-Chu Lin, Wu-Ching Uen, Sheng-Po Hao, Chen-Yu Hsiao, Hung-Chih Lai
Journal: Journal of Clinical Oncology (2019)

e17514 Background: The 1 st line treatment of recurrent and/or metastatic head and neck squamous cell carcinoma (R/M SCCHN) was EXTREME regimen established by Vermorken at al since 2008. Recently in ESMO 2018, Keynote-048 presented frontline pembrolizumab monotherapy or combined chemotherapy had a better overall survival than EXTREME regimen, though with poor PFS (3.2m-3.4m) and response rate (19-23%). But chemotherapy plus pembrolizumab showed a shorter duration of response than the pembrolizumab alone. Therefore, role of chemotherapy as a partner of IO is debated. We presented a retrospective report of triple combination treatment of cetuximab, low-dose chemotherapy and anti-PD1 check-point inhibitor for R/M SCCHN patients as a e-publication in ASCO 2018. This is a update report. Methods: We retrospectively reviewed charts of R/M SCCHN patients who started triple combination of cetuximab, low-dose chemotherapy and anti-PD1 therapy during the period of Feb. 2017 till Jan.31 2018. The contents of combinations, previous treatments, duration of combination treatments, best response, and adverse effects were recorded. Data cutoff is Jan.15 2019. Results: Total 15 patients reviewed. The mean age was 55.4 years (age range 32 – 71 years). Previous treatments included chemotherapy (80%), anti-EGFR (33.3%), anti-PD1 check-point inhibitor (53.3%). The median duration of follow up was 434 days (range 187–707 days). Complete response was observed in 3 patients (20%), partial response in 7 patients (46.7%), stable disease in 4 patients (26.6%) and disease progression in 1 (6.6%). Objective response rate(CR+PR) observed was 66.7%. Clinical benefit rate(CR+PR+SD) observed was 93.3% . Dose of Cetuximab was 250-500mg/m 2 every 2-3 weeks. Combination of chemotherapy included PF, TP, or docetaxel monotherapy. Doses were Cisplatin 30-50mg/m 2 , 5-FU 600-1000mg/m 2 , or docetaxel 20-30mg/m 2 ; all in every 2-3 weeks. Anti-PD1 immune check-point inhibitors included Nivolumab 1-3mg/kg or Pembrolizumab 1-2mg/kg, every 2-3 weeks. Six patients (40%) died: 2 due to progression of disease, 1 due to tumour bleeding, 2 due to pneumonia, and 1 due to fungemia. Conclusions: Our real-world report might suggest a possible role of ADCC effect of cetuximab and less-toxic chemotherapy as a partner of IO. Further prospective study of triple combination therapy with biomarker evaluation is recommended.
CALGB (Alliance) 40603: Long-term outcomes (LTOs) after neoadjuvant chemotherapy (NACT) +/- carboplatin (Cb) and bevacizumab (Bev) in triple-negative breast cancer (TNBC).
Authors: William M. Sikov, Mei-Yin Polley, Erin Twohy, Charles M. Perou, Baljit Singh, Donald A. Berry, Sara M. Tolaney, George Somlo, Elisa R. Port, Cynthia X. Ma, Charles S. Kuzma, Eleftherios P. Mamounas, Mehra Golshan, Jennifer Ruth Bellon, Deborah E. Collyar, Olwen Mary Hahn, Clifford A. Hudis, Eric P. Winer, Ann H. Partridge, Lisa A. Carey
Journal: Journal of Clinical Oncology (2019)

591 Background: Both Cb and Bev demonstrate activity when combined with standard chemotherapy in TNBC. CALGB 40603 is a 2x2 randomized trial that previously demonstrated that adding Cb to NACT significantly increased pathologic complete responses in the breast/axilla (pCR), while adding Bev did not (Sikov, JCO 2015). Here we report 5-year LTOs and assess factors that influenced them. Methods: 443 patients with clinical stage II-III previously untreated TNBC received 12 weeks of paclitaxel (wP) +/- Cb then dose-dense AC, +/- Bev before surgery. The primary endpoint was pCR. Analyses of LTOs (event-free survival (EFS), distant recurrence-free interval (DRFI) and overall survival (OS)), impact of residual cancer burden and other variables were secondary. Results: Median follow-up was 5.7 years (y); 5y EFS was 70.9% (95% CI; 66.7%-75.4%), DRFI 76.3% (72.3%-80.5%) and OS 76.9% (72.9%-81.2%). Pretreatment clinical stage and achieving pCR correlated with LTOs, while age, race, subtype (basal-like vs. not) and tumor grade did not. Among pCR 5y EFS was 86.4% vs. 57.5% for non-pCR (HR 0.28, 0.19-0.43), OS was 88.7% vs 66.5% (HR = 0.28, 0.17-0.44). This relationship was similar in all trial arms. Any residual disease conferred poorer outcome; compared with pCR/Residual Cancer Burden (RCB) 0, EFS HRs were 2.29 (1.32-3.97), 3.01 (1.90-4.74), and 9.67 (5.66-16.51) for RCBI, II and III, respectively. There were no improvements in LTOs with Cb (EFS HR 0.99, 0.70-1.40) or Bev (EFS HR 0.91, 0.64-1.29). In an exploratory analysis, receipt of ≥11 doses of wP was associated with better EFS (HR 1.92, 1.33-2.77); this was particularly notable in Cb-treated arms. Conclusions: As expected, regardless of treatment arm pCR was associated with markedly better LTOs, and pts with any residual disease had significantly worse outcomes. The addition of Cb or Bev to standard NACT for TNBC did not improve LTOs in this trial, although it should be noted that the trial was not powered for this endpoint. Omission of chemotherapy doses may result in poorer outcomes, especially among Cb-treated pts, which may warrant further evaluation. Support: U10CA180821; U10CA180882; Genentech; https://acknowledgments.alliancefound.org ; NCT00861705 Clinical trial information: NCT00861705.
Socioeconomic contributions to clinical outcome by HPV status in squamous cell carcinomas of the head and neck (SCCHN): An analysis of NCDB.
Authors: Jennifer Aline Marks, Jeffrey M. Switchenko, Conor Ernst Steuer, Sara Herrin, Martha A. Ryan, Mihir Patel, Mark El-Deiry, Jonathan Jay Beitler, Dong Moon Shin, Theresa Wicklin Gillespie, Nabil F. Saba
Journal: Journal of Clinical Oncology (2019)

e18214 Background: HPV association remains one of the most important predictors of clinical outcome in SCCHN. We aimed to determine whether the relationship between HPV status and overall survival (OS) varied by certain socioeconomic factors. Methods: Data were obtained from the National Cancer Database (NCDB). We examined the relationship between OS and HPV status, controlling for demographics and socioeconomic variables (insurance, income, education, urban/rural, great circle distance, and/or distance to treatment facility of 0-10, 10-50, and &gt; 50 miles). Results: HPV status modified the relationship between insurance status (p = 0.011), urban/rural residence (p = 0.041), and overall survival, controlling for age, race, sex, and clinical stage. Whereas for HPV- patients, government insurance conferred a lower risk of death compared to no insurance (HR: 0.86, 95% CI: 0.75-0.99, p = 0.038); this finding did not hold for patients with HPV related disease (HR: 0.97, 95% CI: 0.80-1.18, p = 0.781). For patients with HPV related SCCHN, those living in rural areas have significantly higher risk of death compared to those living in metro areas (HR: 1.55, 95% CI: 1.17-2.05, p = 0.002), which did not hold for patients with HPV unrelated SCCHN (HR: 0.94, 95% CI: 0.68-1.30, p = 0.703). Conclusions: Despite HPV’s prospective prognostication, patients with HPV + SCCHN who live in rural environments have a higher risk of death likely from lack of physical access to care. This finding did not hold for HPV negative population, presumably because of their worse outcomes at baseline, and their struggle for access to care regardless of physical location.
Randomized phase II study of second-line modified FOLFIRI with PARP inhibitor ABT-888 (Veliparib) (NSC-737664) versus FOLFIRI in metastatic pancreatic cancer (mPC): SWOG S1513.
Authors: E. Gabriela Chiorean, Katherine A Guthrie, Philip Agop Philip, Elizabeth M. Swisher, Florencia Jalikis, Michael J. Pishvaian, Jordan Berlin, Marcus Smith Noel, Jennifer Marie Suga, Ignacio Garrido-Laguna, Dana Backlund Cardin, Danika L. Lew, Andrew M. Lowy, Howard S. Hochster
Journal: Journal of Clinical Oncology (2019)

4014 Background: PC is characterized by DNA Damage Repair (DDR) deficiencies, including in BRCA1/2, ATM, and FANC genes. Given preclinical synergism between veliparib with irinotecan, safety and preliminary efficacy, we designed a randomized phase II study of mFOLFIRI (no 5-FU bolus) + veliparib vs FOLFIRI alone for 2nd line mPC patients (pts). Methods: Eligible pts had mPC, adequate organ function, ECOG PS 0-1, and 1 prior non-irinotecan systemic therapy.143 pts were to be randomized (1:1) to veliparib vs control. Primary endpoint was overall survival (OS). All pts had blood and tumor biopsies at baseline to assess germline and somatic BRCA1/2 mutations (integrated), and homologous recombination (HR) or DDR biomarkers (exploratory). Results: 123 pts were accrued between 09/2016 to 12/2017, and 108 were included in this analysis. 117 pts were biomarker evaluable: 109 blood/106 tumors. 11 cancers (9%) had HR deficiency (HRD), including 4 germline ( BRCA1, BRCA2, ATM) and 7 somatic mutations ( BRCA2, PALB2, ATM, CDK12). Additional 24 cancers (20%) had germline (n = 11, e.g., FANC, BLM, SLX4, CHEK2) or somatic mutations (n = 13, e.g., FANC, BLM, POLD1, RIF1, MSH2, MSH6) in other DNA repair genes, not classified as HRD. A planned interim futility analysis at 35% of expected PFS events determined the veliparib arm was unlikely to be superior to control. Most common grade 3/4 treatment related toxicities were neutropenia (33% vs 20%), fatigue (19% vs 4%), and nausea (11% vs 4%), for veliparib vs control. Treatment exposure was similar for veliparib vs control: median 4 cycles (range 1-31 vs 1-32). Median OS was 5.1 vs 5.9 mos (HR 1.3, 95%CI 0.9-2.0, p = 0.21), and median PFS was 2.1 vs 2.9 mos (HR 1.5, 95%CI 1.0-2.2, p = 0.05) for veliparib vs control arms, respectively. Correlations of gene mutations and signatures with efficacy outcomes will be presented. Conclusions: Nearly 30% of mPC pts had DNA repair gene abnormalities, including 9% with HRD. Veliparib increased toxicity and did not improve OS when added to mFOLFIRI in biomarker unselected pts. BRCA1/2 and DDR biomarkers will be correlated with efficacy to inform patient selection for future PARP inhibitor clinical trials. Clinical trial information: NCT02890355.
Case 11-1984
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, G. L. Snider, N. L. Harris
Journal: New England Journal of Medicine (1984)

Presentation of CaseA 41-year-old man was admitted to the hospital because of a mediastinal mass and the superior-venacava syndrome.He was well until 10 years earlier, when x-ray films of the chest showed bilateral hilar lymphadenopathy and a coarse reticulonodular pattern in both lungs, more marked in the upper lobes (Fig. 1). Microscopical examination of a scalene-lymph-node-biopsy specimen, performed elsewhere, was reported to reveal sarcoidosis. No treatment was administered. Another x-ray film of the chest, obtained two years later, disclosed widening of the mediastinum, with right paratracheal and left mediastinal lymphadenopathy; the pulmonary reticulonodular pattern was unchanged. Four years . . .
ACCURACY: phase (P) 2 trial of AL101, a pan-Notch inhibitor, in patients (pts) with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) with Notch activating mutations (Notch<sup>act mut</sup>).
Authors: Renata Ferrarotto, Alan Loh Ho, Lori J. Wirth, Edith Dekel, Russell W. Walker, Andrea Leninka Vergara-Silva
Journal: Journal of Clinical Oncology (2019)

TPS6098 Background: Notch signaling plays a key role in tumorigenesis. Notch cleavage by γ-secretase frees the Notch intracellular domain, which promotes the expression of target genes involved in cancer. AL101, a small molecule, is a γ-secretase inhibitor that potently inhibits Notch1-4, resulting in robust antitumor activity in vivo (PMID 26005526), including ACC xenograft models with Notch act mut (Ferrarotto, AACR 2019, Abstr 4885). Three P1 trials tested AL101 as monotherapy or in combination regimens in &gt; 200 solid/hematologic cancer pts. In the P1 trial of AL101 monotherapy, conducted in 94 pts with advanced/metastatic solid tumors refractory to standard therapies (Tx), AL101 was generally well tolerated, with manageable AEs, and the recommended P2 dose was 4 mg IV once weekly (QW; El-Khoueiry, ASCO 2018, Abstr 2515). 4 pts had objective responses, 2 of those had Notch mut (1 of which had ACC). ACC, a rare cancer that most commonly develops in the major salivary glands, but can also arise in minor salivary glands in the trachea, lacrimal gland, and other sites, is refractory to chemotherapy, with a high recurrence rate. Notch act mut are found in a subset of ACC pts (11%–22%), with particularly aggressive disease and poor prognosis. There is no proven active treatment for R/M ACC pts (PMID 27870570). Methods: ACCURACY (NCT03691207) is an open-label, single-arm, multicenter study of AL101 (4 mg IV QW) in pts with R/M ACC (bone-exclusive disease included) with known Notch1-4 act mut . Pts with disease progression within 6 months of enrollment or newly diagnosed metastatic pts are allowed; pts who received &gt; 3 prior systemic Tx are excluded. Primary endpoint: ORR by RECIST v1.1 (or modified MDA bone criteria), by independent review committee (IRC). Secondary endpoints: ORR by investigator review (IR), duration of response by IRC and IR, PFS by IRC, OS, and safety. Per the Simon optimal design, 12 pts are enrolled in stage 1; if ≥2 pts respond, 24 additional pts are enrolled in stage 2. If ≥4 pts in stage 2 respond, the trial is deemed positive. This design yields 5% type I error rate and 80% power, if ORR is 25%. 4 of planned 36 pts have been enrolled as of 2/12/19. Clinical trial information: NCT03691207.
Use of immunotherapy for stage-III and IV melanoma and likelihood of regional and distant lymph node resection and surgical resection for distant metastasis.
Authors: George Molina, Gyulnara G. Kasumova, Motaz Qadan, Genevieve Marie Boland
Journal: Journal of Clinical Oncology (2019)

9558 Background: Immunotherapy (IMT) for stages-III and IV melanoma has dramatically changed overall prognosis and treatment strategies. The aim of this study was to evaluate if use of IMT significantly changed the likelihood of regional/distant lymph node (LN) resection and surgical resection for distant metastases (DM) among patients with stages-III and IV melanoma, respectively, in the pre- and post-2011 era. Methods: The National Cancer Database (2004-2015) was used to evaluate the likelihood of regional/distant LN resection and surgical resection for DM among patients with stages-III and IV melanoma, respectively, with use of IMT. Multivariable stepwise with forward selection Poisson regression with robust standard errors was used to adjust for potential confounders (age, gender, race, year of diagnosis, Charlson-Deyo Score, facility type, facility location, insurance status, 2012 median income quartile, and 2013 urban/rural status). A stratified analysis was performed to evaluate differences among facility type. Results: There were 28,847 patients (median age 62 (IQR 53-73); 36.3% female) with stage-III melanoma and 14,443 patients (median age 66 (IQR 56-76); 31.7% female) with stage-IV melanoma. Overall, 24.3% (n = 7,018) and 17.0% (n = 2,459) with stage-III and IV melanoma, respectively, received IMT. The adjusted relative risk (aRR) of regional/distant LN resection among patients with stage-III melanoma was significantly higher with use of IMT (aRR 1.16, 95% CI 1.05–1.28, P = 0.004), while the aRR of surgical resection for DM was significantly lower with use of IMT for stage-IV melanoma (aRR 0.85, 95% CI 0.78–0.92, P &lt; 0.001). Stratified analysis demonstrated that the findings were principally reflective of academic/research hospitals. Conclusions: The higher likelihood of regional/distant LN resection in stage-III melanoma may be due to the curative role of surgery and preceded the post-MSLT-II era. Conversely, in stage-IV melanoma, surgery may be limited to resectable oligometastatic disease given the durable and systemic benefit of first-line IMT.
Clinical implication of telomere length-related polymorphisms in gastric cardia adenocarcinoma.
Authors: Nasha Zhang, Ming Yang
Journal: Journal of Clinical Oncology (2019)

e15502 Background: Aberrant telomere lengthening is a critical feature of malignant cells. Short leukocyte telomere length (LTL) confers elevated risk of gastric cardia adenocarcinoma (GCA). Multiple genome-wide association studies (GWAS) identified various single nucleotide polymorphisms (SNPs) associated with LTL in different ethnic populations. However, it remains largely unexplored how these genetic variants are involved in GCA susceptibility. Methods: We systematically screened GWAS-identified candidate SNPs and tested the impact of thirty polymorphisms in genes associated with interindividual LTL variation on GCA using two-stage case-control comparisons consisting of 1,024 GCA patients and 1,118 controls. Results: We observed that CXCR4 rs6430612, TERT rs10069690 and rs2853676 as well as VPS34 rs2162440 are significantly associated with GCA development. A 0.64-fold decreased risk of GCA is associated with the CXCR4 rs6430612 CT genotype compared with the CC genotype ( P= 0.002). On the contrary, the TERT rs10069690 TT genotype carriers had a 1.83-fold increased risk to develop GCA compared to the CC genotype carriers ( P= 5.8×10 -6 ). We also detected a 2.17-fold increased OR for GCA that was associated with the TERT rs2853676 TT genotype ( P= 2.6×10 -6 ). In addition, the odds of having the VPS34 rs2162440 GA genotype in GCA patients was 1.35 compared with the GG genotype ( P= 0.002). In stratified analyses, the association between TERT rs10069690 polymorphism and GCA was more pronounced in nonsmokers ( P interaction =9.7×10 -5 ) and nondrinkers ( P interaction = 4.6×10 -5 ). Conclusions: Our results highlight the importance of both LTL and LTL-related genetic variants to GCA predisposition.
Impact of gender on the safety profile of chemotherapy plus bevacizumab in mCRC: A pooled analysis of TRIBE and TRIBE2 studies.
Authors: Gemma Zucchelli, Roberto Moretto, Marta Schirripa, Rossana Intini, Daniele Rossini, Daniele Santini, Claudio Pizzo, Carlotta Antoniotti, Beatrice Borelli, Federica Marmorino, Federica Urbano, Valentina Burgio, Michela Libertini, Michele Prisciandaro, Angela Buonadonna, Sara Bustreo, Giacomo Allegrini, Vincenzo Ricci, Chiara Cremolini, Alfredo Falcone
Journal: Journal of Clinical Oncology (2019)

3534 Background: Based on retrospective experiences, gender seems to affect the safety profile of chemotherapy (CT), with a higher incidence of CT-related adverse events (AEs) among females than males. Here we focus on the impact of gender on the toxicity of FOLFOXIRI/bevacizumab (bev) as compared with doublets (FOLFOX or FOLFIRI)/bev in two randomized phase III studies by GONO: TRIBE and TRIBE2. Methods: The risk of experiencing CT-related AEs in males and females was estimated in univariable analysis in the overall safety population and according to treatment arms (doublets/bev and FOLFOXIRI/bev). In order to assess the independent weight of gender on the risk of developing AEs, multivariable logistic regression models were built. Results: Among 1187 patients enrolled in TRIBE and TRIBE2 studies, 1176 (684 males, 58%, and 492 females, 42%) were included in the safety population. Overall, women had a significantly higher risk of CT-related AEs, in particular gastrointestinal and hematologic AEs, asthenia and alopecia, independently of the treatment arm. The risk of CT-related AEs was increased with FOLFOXIRI/bev vs doublets/bev independently of gender (p for interaction: 0.329). Notably, among women treated with FOLFOXIRI/bev 50% and 68% experienced any grade of vomiting and nausea, respectively. Conclusions: Female mCRC patients have a higher risk to develop CT-related AEs. In women treated with FOLFOXIRI/bev the high incidence of nausea and vomiting may suggest the need for an intensification of the antiemetic prophylaxis. [Table: see text]
Abstract 13275: Prognostic Impact of Impaired Admission Glomerular Filtration Rate and Subsequent Contrast-Induced Acute Kidney Injury on Adverse Cardiovascular Event in Acute Coronary Syndromes
Authors: Hisashi Katayama, Kenichiro Otsuka, Tomohiro Yamaguchi, Hirotoshi Ishikawa, Haruo Nakamura, Hisateru Takeda, Kohei Fujimoto, Noriaki Kasayuki, Minoru Yoshiyama
Journal: Circulation (2015)

Introduction: Contrast-induced acute kidney injury (CI-AKI) after percutaneous coronary intervention (PCI) is associated with adverse short- and long-term cardiovascular outcomes in patients with acute coronary syndrome (ACS). However, the association between the reduction in glomerular filtration rate (GFR) at baseline, CI-AKI, and their prognostic significance on cardiovascular outcomes has not been established. Hypothesis: We hypothesized that the decreased GFR on admission would be associated with cardiovascular outcomes in patients with ACS independent of CI-AKI. Methods: This study consists of consecutive 283 ACS patients (67±12 years old, 207 men) underwent primary-PCI. Decreased admission GFR was defined as less than 60 ml/min per 1.73m2. CI-AKI was defined as an increase of serum creatinine more than 25% within 72 hours after PCI. The primary endpoint was the occurrence of major adverse cardiovascular events (MACE) defined as cardiovascular death and non-fatal myocardial infarction. Results: Of the 283 ACS patients, 59 (21%) had CI-AKI. During median follow-up of 2-year, MACE was occurred in 36 (12%, 5.3% per year) patients. Multivariate Cox proportional hazard analysis demonstrated that higher age (hazard ratio [HR], 1.06, 95% confidence interval [CI], 1.02-1.11; p=0.002), decreased admission GFR (HR, 3.3, 95% CI; 1.45-8.02; p=0.004), and CI-AKI (HR, 2.5, CI, 1.10-5.65; p=0.03) were associated with MACE. Kaplan-Meier analysis demonstrated that patients with decreased admission GFR and CI-AKI presented worse outcomes compared with those without decreased admission GFR and CI-AKI (P&lt;0.001) (Figure). Conclusions: Decreased admission GFR and CI-AKI were independent robust predictors of future MACE in ACS patients underwent primary-PCI.