tbuckley/cabot-search huggingface dataset:
A phase III randomized open label study comparing bempegaldesleukin (NKTR-214) plus nivolumab to sunitinib or cabozantinib (investigator's choice) in patients with previously untreated advanced renal cell carcinoma.
Authors: Nizar M. Tannir, Neeraj Agarwal, Sumanta K. Pal, Maria Nirvana Formiga, Jun Guo, Daniel J. George, Mary Ann Tagliaferri, Alison L. Hannah, Jenny Yanzhen Zhang, Bridget A. O'Keeffe, Daniel C. Cho
Journal: Journal of Clinical Oncology (2019)

TPS4595 Background: Bempegaldesleukin (NKTR-214) is a CD122-preferential IL-2 pathway agonist that stimulates proliferation and activation of tumor antigen-specific CD8 + T cells and natural killer cells within the tumor microenvironment and increases PD-1/PD-L1 expression. These properties make bempegaldesleukin (NKTR-214) a potentially promising agent for combination therapy with checkpoint inhibitors that target and inhibit the PD-1/PD-L1 pathway. In phase 1 studies, NKTR-214 plus nivolumab demonstrated encouraging objective response rates (ORR) in first-line renal cell carcinoma (RCC) and an acceptable safety profile. Immunotherapy with NKTR-214 plus nivolumab may lead to greater clinical benefit than tyrosine kinase inhibitors (TKIs), standard-of-care agents, in this patient population. Methods: This multicenter, randomized, open-label phase 3 study (NCT03729245) will evaluate the efficacy and safety of bempegaldesleukin (NKTR-214) plus nivolumab compared with investigator’s choice of TKI (sunitinib or cabozantinib) in patients with previously untreated advanced or metastatic RCC with clear cell component. Exclusion criteria include active brain metastasis and autoimmune disease. Approximately 600 patients will be randomized in a 1:1 ratio, stratified by PD-L1 status (≥1% vs &lt; 1% or indeterminate), International Metastatic RCC Database Consortium prognostic score (1-2 [intermediate risk] vs 3-6 [poor risk]); and TKI (sunitinib or cabozantinib; cabozantinib percentage to be capped at 50%). Combination therapy will consist of bempegaldesleukin (NKTR-214) 0.006 mg/kg intravenously (IV) every 3 weeks (Q3W) plus nivolumab 360 mg IV Q3W until progression or death or maximum of 2 years. TKI therapy will consist of sunitinib 50 mg orally once daily (QD) for 4 weeks followed by 2 weeks off or cabozantinib 60 mg orally QD. Primary objectives are ORR by blinded independent central radiology (BICR) assessment and overall survival. Secondary objectives are progression-free survival by BICR, safety, predictive value of PD-L1 expression, and quality of life. Enrollment is ongoing. Clinical trial information: NCT03729245.
Cancer patients: Assessing awareness, attitudes and claimed behavior around key decision points upon being diagnosed.
Authors: Kerri Lehrhaupt, Lori Tauber Marcus, Anne Quinn Young, Jenny Isaacson, Marc Hurlbert, Colleen McKenna, Linda Wenger, Kathy Giusti
Journal: Journal of Clinical Oncology (2019)

e23052 Background: As precision medicine becomes increasingly important in oncology, patients need to be educated on making decisions at diagnosis to optimize their outcomes. The HBS Kraft Precision Medicine Accelerator is working with national cancer organizations to understand and address gaps in knowledge and action. Informed by prior patient and physician research, the Accelerator developed the Right Track framework, which addresses the unmet educational needs of patients as they navigate their journey. Methods: Participants with newly diagnosed cancer were recruited by the 5 participating foundations from their databases of affiliated patients (MMRF: n = 63, PanCAN: n = 202, LUNGevity: n = 51, PCF: n = 71, MBC Alliance: n = 66). Inclusion criteria included currently living in the US, 25 years or older, diagnosed with a qualifying cancer in the past 12 months (past 18 months for LUNGevity), self-reported as being at least somewhat knowledgeable in their disease, and self-reported as having some input in treatment decisions. The study was conducted by Kantar Health and sponsored by the HBS Kraft Precision Medicine Accelerator. The fielding was conducted in October 2018. Potential respondents were e-mailed an invitation to complete a 20-minute online survey. Potential respondents were also exposed to an invitation via social media from the participating study sponsors. The respondents were asked a series of customized questions that assessed their awareness and behavior on items within each of the four pillars of the Right Track framework. Results: Descriptive analyses were conducted on each of the four pillars (Right Team, Right Tests, Right Treatment, Sharing at Every Step) and it was found that educational gaps exist across all five cancers. Patients require guidance on selecting a knowledgeable team and facility, understanding their specific cancer sub-type and genomic information, participation in clinical trials and the importance of sharing their data. Conclusions: There is a strong need for patient advocacy foundations to work as unbiased, patient-focused organizations, such that they are well-positioned to help close these knowledge gaps.
Frequency of discordance in programmed death ligand 1 (PD-L1) expression between primary tumors and paired distant metastases in advanced cancers: A systematic review and meta-analysis.
Authors: Chia Ching Lee, Ivan Weng Keong Tham, Char Loo Tan, Jeffrey Lum, Jeremy Chee Seong Tey, Yu Yang Soon
Journal: Journal of Clinical Oncology (2019)

e14290 Background: Randomized trials have demonstrated that PD-L1 expression in tumor cells predicts for response to PD-1 or PD-L1 checkpoint inhibitors in advanced cancers. However, the frequency of discordance in PD-L1 expression between primary tumors and paired distant metastases is currently unclear. We aimed to determine the discordance rate of PD-L1 expression between primary tumor and paired distant metastases in advanced cancers. Methods: We searched MEDLINE and EMBASE for eligible studies. We noted the discordance rate (positive-to-negative or vice versa) and performed subgroup analyses based on the PD-L1 expression in primary tumor, locations of primary tumor and distant metastases, positivity thresholds and type of antibody used for testing. We used QUADAS-2 tool to assess the methodologic quality of the included studies. We performed the meta-analysis using the logistic-normal random effects model. Results: We identified 11 eligible studies including 351 cases of lung, colorectal, breast and ovarian cancers. Nine studies were judged to have low risk of bias in their methodological quality. The overall discordance rate in PD-L1 expression between primary tumor and paired distant metastases was 28% (95% confidence interval (CI) = 18-41) with significant heterogeneity among the studies (chi-square test P-value &lt; 0.0001). There was no statistically significant differences in discordance rates between the subgroups: PD-L1-positive (40%, 95% CI = 21-63) vs PD-L1-negative primary tumors (21%, 95% CI = 12-34), lung primary (31%, 95% CI = 14-55) vs colorectal/ breast/ ovarian primary (27%, 95% CI = 19-37), central nervous system metastases (22%, 95% CI = 8-47) vs liver/ lung/ pleural/ peritoneum metastases (34%, 95% CI = 24-46); 1% (23%, 95% CI 16-33) vs 5% positivity threshold (33%, 95% CI 11-68); E1L3N (42%, 95% CI 10-82) vs SP142 antibody (27%, 95% CI 20-36). Conclusions: The discordance in PD-L1 expression between primary tumors and paired distant metastases is close to 30%, which could potentially affect response to immunotherapy. Further works exploring the mechanisms and impact of this discordance are warranted.
Quality of life and tumor location in patients with desmoid tumors: Data from the desmoid tumor research foundation natural history study.
Authors: Kelly A Mercier, Lynne Hernandez, Vanessa Boulanger, Allison Seebald, Suzanne Rossov, Kelsey Milligan
Journal: Journal of Clinical Oncology (2019)

e18291 Background: Desmoid tumors (DTs) are sarcoma, known to invade surrounding tissues, compromising organ function and complications. As few as 5 per 1 million people are diagnosed with DTs annually, which may be an underestimate of the actual affected population due to difficulty in correctly diagnosing the disease. To improve awareness of DTs and better inform treatment development, DTRF, in partnership with the NORD, launched the DTRF patient registry and natural history study. Here, we describe patient demographics, tumor location, and QOL in registry patients. Methods: The registry launched September 2017 and contains 15 surveys covering diagnostics, disease, treatment, care management, and quality of life. As of January 2019, 357 patients have completed 2,371 surveys. Results: Registry participants are mostly white (88%, 313/357), female (81%, 277/343), and reside in 27 countries with 80% (285/357) US-based. Median age at diagnosis is 33 and the time from onset of symptoms to diagnosis was more than 1 year for 54% (189/352). DT location was reported for 119 respondents at time of data collection. Most prevalent locations were joint /extremities (39%, 47/119), intra-abdominal (24%, 28/119), and chest wall (24%, 29/119). Multiple locations were indicated for 22% (26/119). QOL reported as very good or excellent ranged from 28% to 60%, depending on DT location. Conclusions: Patients with DTs have varied QOL and tumor locations. Data collection through the study is ongoing. [Table: see text]
Differences in pathology and mutational status among colorectal cancer (CRC) patients pre-, post-, and during screening age.
Authors: Gustavo Dos Santos Fernandes, Allan Andresson Lima Pereira, Gabriella Pereira Braga, Brenda Pires Gumz, Marcela Crosara Alves Texeira, Cintia do Couto Mascarenhas, Daniel da Motta Girardi, Adriana Paula de Castro Barrichello, Heinrich Seidler
Journal: Journal of Clinical Oncology (2019)

3596 Background: Screening protocols for CRC are broadly recommended and effective in reducing mortality. However, populations from different age groups can harbor distinct pathological and molecular profiles that can also be influenced by screening and polyp resection, especially in older ages. Methods: We retrospectively analyzed tumors from stage IV CRC patients from a central pathology laboratory in Brazil that is a reference for mutational profiling countrywide. Patients were classified into age groups as the following: pre-screening (PrSA; &lt;45yo), screening(SA; 45-75yo) and post-screening age (PoSA; &gt;75yo). Every tumor has been centrally reviewed by the pathologist. Groups were compared regarding clinicopathologic features and presence of RAS and BRAF mutations. Results: We included 1244 pts (164 PrSA, 919 SA and 161 PoSA). There were no difference among groups regarding sidedness(p= .68)and KRASmutations (p=.0.97). Stage IV at diagnose (p =.001), presence of signet-ring cell component (p&lt; .001) along with poorly differentiated tumors (p= .006) were most found on young patients, while BRAFand NRASmutations where significantly more common among PosSA (table). Conclusions: PosSA and PreSA CRCs seem to present a distinct profile from SA populations, including differences in the molecular and pathologic aspects. This could impact the frequency of screening tests among different age groups. [Table: see text]
Neoadjuvant chemotherapy with docetaxel, carboplatin and biosimilar trastuzumab in Her2-positive early breast cancer.
Authors: Mohammed Oukkal, Souad Challal, Nawel Abed Benmelha, Nabil Benachenhou, Mohcen Wahib Boubnider, Amal Kouchkar, Nadia Terki, Ghania Benkhedda, Ghania Brahimi, Roza Belkaid, Kamel Bouzid
Journal: Journal of Clinical Oncology (2019)

e12080 Background: Evaluation of the histological response after neoadjuvant chemotherapy with Docetaxel-carboplatin and bio similar Trastuzumab (CANMAB 150mg) in Her2 positive breast cancer. The primary end point was pathologic complete response (pCR) rate, determined from surgical specimens. Methods: Between March 2017 and June 2018, we treated 39 patients with Her2-positive breast cancer satge II (61,5%), III (38,5%), with a neoadjuvant schedule of docetaxel (75 mg/m 2 ), carboplatin (AUC 6) and biosimilar trastuzumab (CANMAB 150mg: 8 mg/kg loading dose then 6 mg/kg) every 3 weeks. Patients were diagnosed at a mean age of 48 years; 52,28% had hormone receptor-positive tumors and 87,17% of patients were node positive. All pts received 6 cycles of chemotherapy followed by surgery and one year of biosimilar trastuzumab. Results: We report the preliminary results of a prospective study on the use of the biosimilar trastuzumab combined with preoperative chemotherapy in Her2 positive breast cancer. Thirty nine patients (100%) completed six cycles of therapy. Surgery was breast conservative in 6 (15,38%) of 39 patients. Fifteen of the Thirty one patients (48%) achieved a pCR, Twelve of the twenty six node-positive patients (46,15%) experienced nodal conversion. There was a significantly lower response in HR-positive patients compared to HR-negative ones (26,7 vs 73,33%). No case of congestive heart failure was observed. Conclusions: The use of biosimilar trastuzumab with docetaxel and carboplatin achieved promising efficacy, with a good pCR rate (48%) in stage II or III Her2-positive breast cancer.
ILLUMINATE 301: A randomized phase 3 study of tilsotolimod in combination with ipilimumab compared with ipilimumab alone in patients with advanced melanoma following progression on or after anti-PD-1 therapy.
Authors: Marcus O. Butler, Caroline Robert, Sylvie Negrier, Gino Kim In, John WT Walker, Ivana Krajsova, Victoria Atkinson, Johan Hansson, Ellen Kapiteijn, Carmen Loquai, Heather May Shaw, Tina Cheng, Sandrine Mansard, Jean Jacques Grob, Massimo Guidoboni, Minal Mehta, Paolo Antonio Ascierto, Adi Diab
Journal: Journal of Clinical Oncology (2019)

TPS9599 Background: Tilsotolimod (IMO-2125) is a Toll-like receptor (TLR) 9 agonist with potent immunostimulating activity. In an ongoing Phase 1/2 clinical study in patients with advanced melanoma who progressed on or after anti-PD-1 therapy (NCT02644967), intratumoral (IT) tilsotolimod with ipilimumab was well-tolerated, demonstrating durable responses (including complete response &gt; 21 months), dendritic cell activation, type I interferon response, CD8+ T-cell proliferation in responders, and an abscopal effect. Methods: ILLUMINATE 301 (NCT03445533) is a randomized phase 3 global, multi-center, open-label study of IT tilsotolimod (8 mg) in combination with ipilimumab (3 mg/kg) versus ipilimumab monotherapy in patients with advanced melanoma and progression on or after anti-PD-1 therapy. Eligible patients are ≥18 years with histologically confirmed unresectable Stage III or Stage IV melanoma, ≥1 measurable lesion accessible for injection (superficial or visceral, the latter with image guidance), ECOG PS ≤1, and adequate organ function. Exclusion criteria include prior TLR agonists, prior ipilimumab (except adjuvant ≥12 weeks before progression), and CNS disease other than stable brain metastases. Patients are randomized 1:1 and stratified by duration of prior anti-PD-1 (≥12 weeks vs &lt;12 weeks), stage (M1c vs other), and BRAF status/prior targeted therapy (TT) (BRAF wildtype vs BRAF mutation+ with TT vs BRAF mutation+ without TT). Primary endpoints are overall response rate (RECIST v1.1) by independent central review and overall survival. Secondary endpoints include durable response rate, time to response, progression-free survival, patient-reported outcomes, and safety. Patients are enrolling at sites in the United States, European Union, Australia, and Canada. References: (1) Haymaker C. Society for Immunotherapy of Cancer Annual Meeting, November 2017, National Harbor, MD; (2) Diab A, et al. European Society of Molecular Oncology Annual Meeting, October 2018, Munich, Germany. Clinical trial information: NCT03445533.
Trametinib for aggressive gliomas in adults with neurofibromatosis type 1.
Authors: Carlos G Romo, Bronwyn L Slobogean, Lindsay Karen Blair, Jaishri O'Neill Blakeley
Journal: Journal of Clinical Oncology (2019)

e13562 Background: Neurofibromatosis type 1 (NF1) is caused by mutations of the tumor suppressor gene NF1 resulting in decreased levels of neurofibromin and dysregulation of the RAS pathway, including MEK/ERK upregulation. NF1 is characterized by multiple benign and malignant tumors. Central nervous system tumors have an overall standardized incidence ratio of 37.5 in population studies with high rates of aggressive gliomas in adults with NF1. The response to standard glioma therapies is mixed. MEK1/2 inhibitors have shown activity in NF1 driven plexiform neurofibromas and low grade gliomas, however, data is lacking about the optimal dose or sequencing of MEK1/2 inhibitors for adults with NF1 associated aggressive gliomas. We present recent experiences with the MEK1/2 inhibitor trametinib in adults with NF1 and aggressive gliomas. Methods: A retrospective chart review was conducted on all adult patients with NF1 and astrocytoma treated with trametinib at the Johns Hopkins Brain Cancer Program between 2016-2018. Results: Three patients met selection criteria. Two received trametinib as initial therapy (2 mg daily). All developed an acneiform rash; one had transient transaminitis requiring temporary discontinuation and subsequent dose reductions. Clinical benefit was achieved associated with two partial radiographic responses. Conclusions: Astrocytomas in adults with NF1 often have a more aggressive course than suggested by histology. The cases presented here demonstrate clinical benefit from single agent MEK inhibition as well as possible synergistic effects with conventional therapies for gliomas in this patient population. These observations highlight the need for further research in this area. [Table: see text]
MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation
Authors: Sara Sdelci, André F. Rendeiro, Philipp Rathert, Wanhui You, Jung-Ming G. Lin, Anna Ringler, Gerald Hofstätter, Herwig P. Moll, Bettina Gürtl, Matthias Farlik, Sandra Schick, Freya Klepsch, Matthew Oldach, Pisanu Buphamalai, Fiorella Schischlik, Peter Májek, Katja Parapatics, Christian Schmidl, Michael Schuster, Thomas Penz, Dennis L. Buckley, Otto Hudecz, Richard Imre, Shuang-Yan Wang, Hans Michael Maric, Robert Kralovics, Keiryn L. Bennett, Andre C. Müller, Karl Mechtler, Jörg Menche, James E. Bradner, Georg E. Winter, Kristaps Klavins, Emilio Casanova, Christoph Bock, Johannes Zuber, Stefan Kubicek
Journal: Nature Genetics (2019)
Outcome of patients with stage 2 or stage 3 seminoma treated with 3 cycles of cisplatin-etoposide chemotherapy (EP120): Updated data from a single center retrospective study.
Authors: Claudia Gardiner, Paul Hutton, Mariam Jafri, Emilio Porfiri
Journal: Journal of Clinical Oncology (2019)

e16061 Background: Metastatic seminoma is eminently treatable with platinum-based chemotherapy with either 3 cycles of BEP—bleomycin (B), etoposide (E) and cisplatin (P)—or 4 cycles of EP, achieving remission in more than 95% of the patients. However, bleomycin has a substantial toxicity profile and can cause life-threatening lung toxicity. Whether similar cure rates can be achieved without exposing patients to bleomycin is still undetermined. We describe our 19-year experience of treating patients with stage 2 or stage 3 seminoma with 3 cycles of EP chemotherapy. Methods: Patients who received 3 cycles of EP120 chemotherapy (50mg/m 2 cisplatin day 1 and 2 and 120mg/m 2 etoposide days 1, 2 and 3 every 3 weeks for 3 cycles) for stage 2 or stage 3 seminoma between 01/03/2000 and 31/05/2015 were identified. Data were retrospectively collected on stage, prognostic group, previous adjuvant treatment, serological and radiological response, time to relapse and subsequent management, progression-free survival (PFS) and overall survival (OS). Results: We identified 115 patients who received EP120 for seminoma and who met the inclusion criteria. Median age was 40 years (range 17-72). All patients were in the good-prognosis group. 103 patients (90%) were diagnosed with stage 2 seminoma, 12 patients (10%) with stage 3 (3 patients stage 3a and 9 stage 3b). 97 patients (84%) presented with stage 2 or 3 seminoma and 18 patients (16%) had progressed to stage 2 or 3 following adjuvant radiotherapy or adjuvant carboplatin chemotherapy for stage 1 disease. Seven patients (6%) with stage 2 seminoma relapsed after EP120 chemotherapy: 2 patients ≤3 months and 5 patients ≥ 3 months. None of the patients with stage 3 disease has relapsed so far. Of the 7 patients who relapsed, 2 received radiotherapy, 4 received TIP (paclitaxel, ifosfamide, cisplatin) chemotherapy and 1 received a combination of TIP chemotherapy and radiotherapy. All patients who relapsed after EP120 are currently in remission. Two of the 115 patients (1.7%) died whilst in remission and of unrelated causes. The 5-year PFS was 94% and the OS was 98%. Conclusions: Our data suggest that patients treated with 3 cycles of EP120 had survival rates similar to patients treated with more aggressive chemotherapy regimens.
Case 36-1989
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Jerome E. Groopman, Judith A. Ferry
Journal: New England Journal of Medicine (1989)

Presentation of CaseA 34-year-old man was admitted to the hospital because of fever, diarrhea, persistent jaundice, and a worsening gait disturbance.The patient was apparently well until four months earlier, when abdominal pain developed and he was admitted to this hospital. He had immigrated from Jamaica 18 years earlier and was employed as a graphics designer. He admitted to taking as many as eight drinks daily on weekends but consumed only four bottles of beer during the week. He denied any history of jaundice, exposure to hepatitis, weight loss, homosexual activity, contact with prostitutes, intravenous drug abuse, receipt of . . .