tbuckley/cabot-search huggingface dataset:
A phase II trial of S-1 plus cisplatin with concurrent proton-beam therapy for locally advanced non-small cell lung cancer.
Authors: Kenji Akita, Hiromitsu Iwata, Hiroyuki Ogino, Yusuke Yamaba, Eiji Kunii, Yuta Mori, Misuzu Yoshihara, Minoru Horiuchi, Yukiko Hattori, Shingo Hashimoto, Koichiro Nakajima, Katsumi Nakamae, Fumiya Baba, Yuta Shibamoto, Jun-etsu Mizoe
Journal: Journal of Clinical Oncology (2017)

e20070 Background: Concurrent chemo-radiotherapy is the standard treatment for locally advanced (LA) non-small cell lung cancer (NSCLC). Recent phase II studies have demonstrated that S-1 plus cisplatin (CDDP) with concurrent radiotherapy yields promising results against LA NSCLC. Proton-beam therapy (PBT) is an alternative modality that is expected to reduce toxic effects against normal tissues compared with X-ray radiotherapy. We conducted a phase II trial of S-1 plus CDDP combined with concurrent PBT for patients (pts) with LA NSCLC. Methods: The eligibility criteria included unresectable stage III NSCLC, chemo-naïve status, PS 0 or 1, and age &lt; 75 years. Pts received CDDP (80 mg/m 2 ) on day 1 and S-1 (30-40 mg/m 2 twice daily) on days 1 to 14, q4w, up to 4 cycles, plus concurrent PBT at a total dose of 70 GyE in 35 fractions for primary lesion and 66 GyE in 33 fractions for lymph node metastasis. PBT was performed using respiratory-gated and image-guided techniques, and adaptive plans were implemented according to a verification plan at 10, 20, and 30 days. Results: Thirty-two pts were enrolled between August 2013 and December 2016. The patient characteristics were as follows: median age, 66 (31-74); male/female, 24/8; PS 0, 26 pts; stage IIIA/IIIB, 19/13; non-squamous histology, 17 (53%). Twenty pts were out of indication for radical chemo-radiation with X rays. All 4 cycles of S-1 plus CDDP could be completed in 24 pts and the median number of cycles was 3.3 (range: 2 to 4). Grade 3/4 toxicities per pt were: neutropenia 28%, anemia 13%, thrombocytopenia 9.4%, fatigue, anorexia, esophagitis, mucositis and enteritis 3.1%, and radiation pneumonitis 0%. One case of febrile neutropenia was observed. PR + CR was achieved in 24 of 28 evaluable pts. The median PFS was 12.5 months, and 2-year OS was 63%, with a median follow-up period of 19.5 (range: 1.5-40.0) months. Conclusions: Concurrent chemo-PBT using S-1 plus CDDP with image-guided and adaptive techniques is considered to be effective and well tolerated for LA NSCLC. Further evaluations in a large randomized controlled trial are warranted.
Phase ib and phase II studies of pembrolizumab (P) with bevacizumab (B) for the treatment of metastatic renal cell carcinoma (RCC): BTCRC-GU14-003.
Authors: Arkadiusz Z. Dudek, Li C Liu, Ajjai Shivaram Alva, Mark Stein, Shilpa Gupta, Costantine Albany, Monika Joshi, Yousef Zakharia, Joshua Michael Lang, James K. Schwarz, Anas Al-Janadi
Journal: Journal of Clinical Oncology (2018)

4558 Background: Hypoxic regions of RCC, impede homing of cytotoxic T cells into tumor. In addition, tumor angiogenesis enhances immunosuppressive activity of MDSC and TAM. Antiangiogenic therapy decreases the number of MDSC and changes polarization of TAM to an immunostimulatory phenotype. We hypothesized that therapy with B will potentiate the immune anti-tumor activity of P. We, therefore, performed phase 1b for safety of P and B, followed by phase 2. Methods: Study population included subjects (age > 18 y) with metastatic clear cell RCC after failure of at least one systemic therapy (phase 1b) or treatment naïve (phase 2). In phase Ib, P (200 mg dose q 3 weeks) was given with B (either at 10 or 15 mg/kg q 3 weeks). Primary endpoint for phase 2 was response rate (RR) (PR or CR) using RECIST v1.1. With assumption of 80% power to detect a 55% improvement in RR of P and B, over historic data with single P activity in RCC (RR of 27%), and an a error of 0.1, 48 subjects were to be accrued to detect RR of 42%. Results: 13 subjects (ages 33-68, median 55) were enrolled to phase 1b study; 11 males. No dose-limiting toxicity have been reported. Best responses (BR) were 5 PR, 6 SD, 1 PD. Median time on treatment was 130 (21-659) days. 200 mg of P and 15 mg/kg of B, given q 3 weeks, was determined to be safe and used in phase 2. 48 subjects (ages 42-84, median 61); 33 males were accrued to phase 2 study. Primary endpoint of RR was reached at 60.9 % (95% CI = 45.4%, 74.9%) with median time on treatment 298 (range 21-741) days. BR: 28 PR, 18 SD, 2 UN. Progression occurred in 20 (41.7%) patients. Median PFS time was 17.0 months (95% CI = 11.3, 24.8). Median OS has not been reached. 12 (25%) died. Most common grade 3 toxicity were hypertension (21%), hyponatremia, proteinuria (9%), adrenal insufficiency, dehydration 6 %), pneumonitis, skin toxicity, weakness, nausea and vomiting (4%), diarrhea, and arthralgia (2 %). There were 2 grade 4 toxicities (hyponatremia and hyperglycemia). There was 1 grade 5 toxicity (heart failure). Presence of tumor infiltrating T cells, but not PD-L1 expression correlated with PR. Conclusions: The 200 mg of P and 15 mg/kg dose of B, given every 3 weeks, is safe and active in metastatic RCC. Clinical trial information: NCT02348008.
Two-year clinical outcomes of de-intensified chemoradiotherapy for low-risk HPV-associated oropharyngeal squamous cell carcinoma.
Authors: Bhishamjit S. Chera, Robert J Amdur, Joel E. Tepper, Bahjat F. Qaqish, David N. Hayes, Jared Weiss, Juneko E. Grilley-Olson, Adam M Zanation, Trevor Hackman, Jose Zevallos, Samip Patel, Nathan Christopher Sheets, Mark Christian Weissler, William M. Mendenhall
Journal: Journal of Clinical Oncology (2017)

6044 Background: We here-in report 2 year cancer control outcomes from a prospective phase II clinical trial evaluating de-intensified chemoradiotherapy (CRT) for patients with favorable risk, HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Methods: The major inclusion criteria were: T0-T3, N0-N2c, M0, HPV or p16 positive, and minimal smoking history. Treatment was limited to 60 Gy intensity modulated radiotherapy with concurrent weekly intravenous cisplatin (30 mg/m 2 ). Patients neither received induction chemotherapy nor definitive surgery. The primary study endpoint was pathologic complete response rate (pCR) based on required biopsy of the primary site and dissection of pretreatment positive lymph node regions, regardless of radiographic response. Secondary endpoint measures included 2 year local control (LC), regional control (RC), cause specific survival (CSS), distant metastasis free survival (DMFS), and overall survival (OS), and patient reported symptoms (PRO-CTCAE) and quality of life (EORTC QLQ-C30 &amp; H&amp;N35). Results: Forty-four patients enrolled and the median f/u was 36 months (range 5-53 months, 93% with &gt; / = 1 year, 88% &gt; / = 2 years). We have previously reported the pCR to be ~ 86%. Two year LC, RC, CSS, DMFS, and OS are the following: 100%, 100%, 100%, 100%, and 95%. All 6 patients who had pathological partial responses are alive with no evidence of disease with a median f/u of 34 months (range 9-48 months). Two patients have died (stroke and glioblastoma). Mean pre and 2-year post EORTC QOL scores were: Global 80/82 (lower worse), Swallowing 11/10 (higher worse), Dry Mouth 16/54, and Sticky Saliva 6/33. 39% of patients required a feeding tube (none permanent) for a median of 15 weeks (5 - 22 weeks). Mean pre and 2 year post PRO-CTCAE (1 to 4 scale, higher worse) scores were: Swallowing 0.4/0.8 and Dry mouth 0.4/1.8. There were no &gt; / = Grade 3 late adverse events. Conclusions: The 2-year clinical outcomes with decreased intensity of therapy with 60 Gy of IMRT and weekly low-dose cisplatin are excellent in favorable risk OPSCC with evidence of better preservation of quality of life as compared to standard therapies. Clinical trial information: NCT01530997 .
Single-agent expansion cohort of lenvatinib (LEN) and combination dose-finding cohort of LEN + etoposide (ETP) + ifosfamide (IFM) in patients (pts) aged 2 to ≤25 years with relapsed/refractory osteosarcoma (OS).
Authors: Nathalie Gaspar, Michela Casanova, Francisco José Bautista Sirvent, Rajkumar Venkatramani, Bruce Morland, Marion Gambart, Estelle Thebaud, Sandra J Strauss, Franco Locatelli, Soledad Gallego Melcon, Adela Canete, Stefan S. Bielack, Claudia Rossig, Isabelle Aerts, Perrine Marec-Berard, Silvija Kraljevic, Seiichi Hayato, Cixin He, Corina E. Dutcus, Quentin Campbell-Hewson
Journal: Journal of Clinical Oncology (2018)

11527 Background: LEN is a multikinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRα, KIT, and RET. In human pediatric OS xenograft models, LEN enhanced the antitumor activity of IFM + ETP. In a phase (Ph) 2 study of sorafenib in pts with unresectable high-grade OS, progression-free survival at 4 months (PFS-4) was 46%. We report emerging data from a Ph 2 single-agent LEN expansion cohort and Ph 1b combination dose-finding cohort of LEN + ETP + IFM in pts with relapsed/refractory OS. Methods: Pts were age 2 to ≤25 years, had relapsed OS, and had < 2 prior VEGF-targeted therapies. The recommended dose (RD; 14 mg/m2) from Ph 1 was used in Ph 2. In Ph 1b, a 20% reduction of LEN (11 mg/m2/day) was used as starting dose in combination with IFM 3000 mg/m2 + ETP 100 mg/m2 daily/3 days. Ph 2 and Ph 1b primary endpoints were PFS-4 per RECIST 1.1 and RD of the combination. Secondary objectives included best overall response (BOR), objective response rate, PFS, safety, and PK. Data cutoff was October 6, 2017. Results: In Ph 2, 16 pts received LEN 14 mg/m2. Median (min, max) number of cycles received was 3.0 (1, 9). Most common any-grade TEAEs were diarrhea, hypothyroidism, and proteinuria (43.8% each). Most common Grade (G) 3 or 4 TEAEs were back pain and dyspnea (12.5% each). One pt discontinued due to TEAEs (myelodysplastic syndrome); 5 of 15 evaluable pts achieved PFS-4 and BOR was PR (n = 1) and SD (n = 7). In Ph 1b, 7 pts received LEN 11 (LEN 11 mg/m2 + IFM + ETP) and 6 pts received LEN 14 (LEN 14 mg/m2 + IFM + ETP). 1 pt had a DLT at LEN 11 (G3 thrombocytopenia) and 2 pts had DLTs at LEN 14 (G4 thrombocytopenia with G3 bleeding in 1 pt; G2 oral dysesthesia, G2 back pain, and G1 muscle spasms in 1 pt). G ≥3 TEAEs occurred in 85.7% and 66.7% of LEN 11 and LEN 14 pts, respectively. No pts discontinued due to TEAEs. BOR was PR (n = 1) and SD (n = 5). AUC at steady state of LEN and distributions of interindividual variability of oral clearance were comparable between LEN single agent and the combination. Conclusions: In Ph 2, LEN at 14 mg/m2 achieved PFS-4 in 5 pts; BOR was PR in 1 pt and SD in 7 pts. In Ph 1b, LEN + chemotherapy had a manageable safety profile. The study is ongoing and updated data will be presented. Clinical trial information: NCT02432274.
C-MET overexpression as a resistance biomarker to epidermal growth factor receptor tyrosine kinase inhibitors in <i>EGFR</i>-mutant non-small cell lung cancer.
Authors: Young Joo Lee, Ji-Youn Han, Geon Kook Lee, Jiin Shin, Seul Ae Yun, Ju Yeon Oh, Sangho Lee, Heung Tae Kim, Jin Soo Lee
Journal: Journal of Clinical Oncology (2016)

e20660 Background: Multiple mechanisms of C-MET activation have been reported in non-small cell lung cancer (NSCLC) including amplification and mutation. C-MET protein overexpression also occurs in 25%-75% of NSCLC and is associated with poor prognosis of NSCLC. This study aimed to evaluate whether C-MET protein expression is associated with the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) in EGFR-mutant NSCLC. Methods: We retrospectively analyzed 1199 consecutive NSCLC patients, who were tested for C-MET expression by immunohistochemistry (IHC) between Nov 2013 and Sep 2015. The staining intensity within tumor tissue was graded on a scale of 0 (negative), 1+ (weak), 2+ (moderate), and 3+ (strong). C-MET positivity was defined as C-MET expression with strong staining intensity (grade 3+) in more than 50% of tumor cells. Among 262 patients with EGFR exon 19 deletions or exon 21 L858R mutation, 83 EGFR-mutant patients received EGFR-TKI as a first line therapy. Results: In total of 1199 tumors, the frequency of each tumor with C-MET grade 0 to grade 3+ was 10.8%, 41.0%, 32.5%, and 15.7%, respectively. C-MET expression was significantly stronger in the tumors with adenocarcinoma than those with squamous cell carcinoma (P< 0.001). In the tumors with adenocarcinoma, EGFR-mutant tumors showed stronger expression of C-MET than EGFR-wild type tumors (P< 0.001) but no difference in C-MET expression by mutation types was observed (P= 0.248). In the first-line EGFR-TKI treatment group, there was no significant difference in response rate to EGFR-TKI between the patients with C-MET positivity (n = 7) and those with C-MET negativity (n = 76) (71% vs. 88%, P= 0.231). However, the median progression-free survival (PFS) to EGFR-TKI was significantly shorter in the C-MET positive group compared with the C-MET negative group (4.3 months vs. 11.9 months, P= 0.015). Conclusions: C-MET overexpression was associated with shorter PFS to EGFR-TKI in the patients with EGFR-mutant NSCLC. C-MET overexpression might be as a biomarker to resistance to EGFR-TKI therapy in this population.
TCT-228 Outcomes After Treatment of Coronary In-Stent Restenosis With Drug-Coated Balloon Versus Drug-Eluting Stent According to the Presence or Absence of Diabetes Mellitus: A Prespecified Analysis of the DAEDALUS Study.
Authors: Daniele Giacoppo, Fernando Alfonso, Bo Xu, Bimmer Claessen, Tom Adriaenssens, Christoph Naber, Maria Perez-Vizcayno, Do-yoon Kang, Ralf Degenhardt, Leos Pleva, Jan Baan, Duk-Woo Park, Runlin Gao, Seung-Jung Park, Jose PS. Henriques, Adnan Kastrati, Robert Byrne
Journal: Journal of the American College of Cardiology (2018)
Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study
Authors: P. Conte, A. Frassoldati, G. Bisagni, A.A. Brandes, M. Donadio, O. Garrone, F. Piacentini, L. Cavanna, F. Giotta, M. Aieta, V. Gebbia, A. Molino, A. Musolino, A. Ferro, R. Maltoni, S. Danese, C. Zamagni, A. Rimanti, K. Cagossi, A. Russo, P. Pronzato, F. Giovanardi, G. Moretti, L. Lombardo, A. Schirone, A. Beano, L. Amaducci, E.A. Bajardi, R. Vicini, S. Balduzzi, R. D’Amico, V. Guarneri
Journal: Annals of Oncology (2018)

Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy.HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary end points included 2-year failure rate and cardiac safety.A total of 1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR is 1.13 (90% CI 0.89-1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-year overall survival (OS) is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90% CI 0.74-1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95% CI 0.22-0.50, P < 0.0001).This study failed to show the non-inferiority of a shorter trastuzumab administration. One-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse.EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.
Low-Dose Radiation Conditioning Enables CAR T Cells to Mitigate Antigen Escape
Authors: Carl DeSelm, M. Lia Palomba, Joachim Yahalom, Mohamad Hamieh, Justin Eyquem, Vinagolu K. Rajasekhar, Michel Sadelain
Journal: Molecular Therapy (2018)

CD19 chimeric antigen receptors (CARs) have demonstrated great efficacy against a range of B cell malignancies. However, antigen escape and, more generally, heterogeneous antigen expression pose a challenge to applying CAR therapy to a wide range of cancers. We find that low-dose radiation sensitizes tumor cells to immune rejection by locally activated CAR T cells. In a model of pancreatic adenocarcinoma heterogeneously expressing sialyl Lewis-A (sLeA), we show that not only sLeA+ but also sLeA- tumor cells exposed to low-dose radiation become susceptible to CAR therapy, reducing antigen-negative tumor relapse. RNA sequencing analysis of low-dose radiation-exposed tumors reveals the transcriptional signature of cells highly sensitive to TRAIL-mediated death. We find that sLeA-targeted CAR T cells produce TRAIL upon engaging sLeA+ tumor cells, and eliminate sLeA- tumor cells previously exposed to systemic or local low-dose radiation in a TRAIL-dependent manner. These findings enhance the prospects for successfully applying CAR therapy to heterogeneous solid tumors. Local radiation is integral to many tumors' standard of care and can be easily implemented as a CAR conditioning regimen.
Patterns of bone scan and pain response following treatment with Ra-223 in metastatic castrate resistant prostate cancer (mCRPC).
Authors: Lindsey Shantzer, Michala Ritz, Bennett B Chin, Jorge Oldan, Aseem Anand, Taofik Oyekunle, Monika Anand, Andrew J. Armstrong, Daniel J. George, Megan Ann McNamara
Journal: Journal of Clinical Oncology (2018)

e17011 Background: Overall survival was improved in men with mCRPC treated with radium-223 (Ra-223) in the phase 3 ALSYMPCA trial; however, bone scans were not performed in this study, and retrospective series suggest variable rates of both soft tissue and bone scan progression over time with Ra-223. In addition, biomarkers of clinical benefit to Ra-223 are needed. Methods: We performed a retrospective chart review of all men with mCRPC who received Ra-223 at the Duke Cancer Institute from June 1, 2013 to June 1, 2015, in order to describe radiographic changes on bone scan during Ra-223. Radionuclide bone scans were reviewed by two radiologists prior to, during, and following Ra-223 treatment. The automated bone scan index (aBSI) was generated at each time point using EXINI boneBSI v. 2. Results: We identified 61 patients (72% white, 28% black, median age 68) with mCRPC who received ≥ 1 dose of Ra-223 (median 5 doses, range 1-6). After Ra-223, 9 of 41 evaluable patients with post-treatment bone scans had 0 new bone lesions and 6 of 41 had resolution of some existing bone lesions. Patients without new bone lesions or with resolution of bone lesions following Ra-223 had lower baseline LDH, PSA, ALP, and aBSI, compared to patients with new or non-resolving bone lesions. 64% (39/61) of men reported improvement in pain during (n = 25) or after (n = 14) Ra-223, including 11 after the 1st dose, 7 after the 2nd, 5 after the 3rd, and 2 after the 4th. 15% (n = 9) experienced pain flare after Ra-223, most often after the 1st dose (n = 8). Pain flare lasted < 7 days in n = 2, 8-14 days in n = 2, 15-28 days in n = 2, and > 29 days in n = 2. There was no association between pain response and bone scan response (p = 0.2031), pain flare and eventual pain response (p = 0.4167), or pain flare and bone scan response (p = 1.000). Conclusions: Ra-223 provides a palliative benefit to men with bone predominant mCRPC. The majority of patients experience improved pain by the 4th dose, and pain flare occurs rarely. We found preliminary evidence that a bone scan response or stabilization with Ra-223 was associated with lower pretreatment levels of key prognostic biomarkers including PSA, LDH, and ALP as well as a lower aBSI.
Impact of palliative care consults on racial disparity in do-not resuscitation (DNR) orders at an urban safety net hospital.
Authors: Nizar Bhulani, Arjun Gupta, M. Elizabeth Paulk, Kiauna Donnell, Valorie Harvey, Joan Cox, John Vernon Cox, Udit N. Verma, Aravind Sanjeevaiah, Naga Koteswari Cheedella, Leticia Khosama, Yull Edwin Arriaga, Samira K. Syed, Syed Mohammad Ali Kazmi, Muhammad Shaalan Beg
Journal: Journal of Clinical Oncology (2018)

10027 Background: Previous studies have suggested that racial disparities exist for DNR orders in cancer patients. We examined racial differences in DNR orders for pancreatic cancer patients in an urban setting safety net hospital with a high proportion of black patient population. Methods: Retrospective analysis was conducted of pancreatic cancer patient records seen at the Parkland Health and Hospital System, Dallas between 1/1999 - 9/2016. Cancer cases and receipt of palliative care were identified from prospectively maintained registries. Demographics, cancer characteristics, DNR order, were abstracted. All statistical analysis was done using IBM SPSS version 24. Results: A total of 455 pancreatic cancer patients were included; mean age was 61 years, 227 (50%) were female, 228 (50%) were white and 202 (44%) were black, 277 (61%) received a palliative care, and 29 (6.4%) had at least one ICU admission. There was no statistically significant difference in palliative care consults between whites and black patients. Do-Not-Resuscitate (DNR) order was placed for 140 (30.8%) patients within 60 days of death. DNR status was significantly associated with cancer stage, admission to the ICU and receiving a palliative care consult (p < 0.001). There was no difference in the rate of DNR order between white and black patients, 29.7% (68/229) white patients and 32.2% (65/202) black patients (p = 0.71). Additionally, age, sex, cancer site or histology were not associated with DNR order. Conclusions: In this single institution study of pancreatic cancer patients there was no racial disparity in DNR orders. This can be explained by a high rate of palliative referrals (61%) and a safety net system which improves access to care. Additional studies are needed to understand determinants of DNR order use. Systems based changes, such as early integration of palliative care and increased access to health services can reduce racial disparities in DNR status of minority cancer patients.