tbuckley/cabot-search huggingface dataset:
High-dose naxitamab plus stepped-up dosing of GM-CSF for high-risk neuroblastoma (HR-NB): Efficacy against histologically-evident primary refractory metastases in bone marrow (BM).
Authors: Brian H. Kushner, Shakeel Modak, Ellen M. Basu, Stephen S. Roberts, Nai-Kong V. Cheung
Journal: Journal of Clinical Oncology (2019)

10024 Background: Cure of HR-NB often requires ablating BM metastases that are chemoresistant and survive 131 I-metaiodobenzylguanidine (MIBG) therapy. BM is ideal for immunotherapy with anti-G D2 antibodies including naxitamab (humanized-3F8; granted FDA’s breakthrough designation in 2018) because of excellent accessibility to antibody, complement, and effector cells. GM-CSF exerts a dose-response effect in antibody-dependent cellular cytotoxicity and significantly improves outcome with murine-3F8 ( JCO 2012;30:426). Methods: We evaluated HR-NB patients with histologically-evident chemoresistant disease in BM, but no soft tissue or prior progressive disease, for response to naxitamab+GM-CSF on protocol (NCT01757626). Cycles comprised naxitamab infused intravenously (30 minutes) x3 (Mon-Wed-Fri) and subcutaneously-administered GM-CSF starting 5 days pre-naxitamab in priming doses of 250µg/m 2 /day, then stepped-up to 500µg/m 2 /day beginning with antibody. Naxitamab was dose-escalated in the phase I portion and 9mg/kg/cycle (~270mg/m 2 /cycle, i.e., &gt; 2.5x dosage of ch14.18) in the phase I/II expansion. BM was assessed post-cycle 2 in aspirates+biopsies from bilateral posterior and anterior iliac crests. Cycles were monthly but were deferred if human anti-human antibody (HAHA) developed. Results: The 19 patients enrolled through 5/2018 were 5m-to-19m (median 7.5m) post-diagnosis and age 2y10m-to-10y1m (median 5y2m). Included were 5 phase I and 14 phase I/II patients. Histology showed primitive NB in 12 and ganglioneuromatous cells in 7 patients. All (100%) patients achieved complete response (CR) in BM. 16 patients also had NB in bone/BM by 123 I-MIBG scan; the latter showed CR in 12 (75%). 11 patients remained progression-free 20+-to-54+ (median 27+) months from enrollment, including 10 treated with anti-NB vaccine. HAHA developed in 2 patients post-cycle 2. Toxicities were as expected ( JAMA Oncol 2018;4:1729). Conclusions: Naxitamab+GM-CSF is effective against chemoresistant NB in BM, supporting further development of naxitamab which is proceeding in a pivotal international trial (NCT02502786). Clinical trial information: NCT01757626.
Phase 2 study of tremelimumab plus durvalumab for previously-treated malignant pleural mesothelioma (MPM).
Authors: Deepti Venkatraman, Adrienne Anderson, Subba Digumarthy, Patrick H. Lizotte, Mark M. Awad
Journal: Journal of Clinical Oncology (2019)

8549 Background: Treatment options are limited for patients (pts) with MPM who experience disease progression after first-line pemetrexed-based chemotherapy. This study was designed to explore the activity of combined CTLA-4 + PD-L1 immune checkpoint inhibition using tremelimumab plus durvalumab in previously-treated MPM. Methods: We conducted a phase 2 study of tremelimumab 75 mg plus durvalumab 1500 mg administered intravenously every 4 weeks for four cycles followed by durvalumab maintenance every 4 weeks. Eligible pts had previously received pemetrexed-based platinum doublet chemotherapy and had measurable disease using modified RECIST criteria for mesothelioma. The primary endpoint was overall response rate (ORR) and secondary endpoints were progression-free survival (PFS), overall survival (OS), and duration of response (DoR) as well as safety and tolerability of this combination. A Simon two-stage design was employed to enroll up to 40 patients if 4 or more responses were observed among the first 19 study patients. Pre-treatment, on-treatment, and optional post-progression biopsies underwent flow cytometric immunoprofiling for correlative studies. Results: Among 19 pts enrolled in this study, the best objective response was a confirmed partial response in one patient (5%), stable disease in 9 pts (47%), progressive disease in 8 pts (42%), and not evaluable in one patient. At a median follow-up of 7.1 months, the median PFS was 2.8 months (95% CI 2.04-5.72), and the median OS was 7.8 months (95% CI 6.24-not reached). Of 17 PD-L1 evaluable cases, 10 (59%) were PD-L1 negative, and 7 (41%) had a PD-L1 tumor proportion score of ≥1%. Treatment was generally well-tolerated and there were no treatment-related study discontinuations or deaths. Flow cytometric immunologic changes over the course of treatment associated with disease control will be presented. Conclusions: Tremelimumab + durvalumab was well-tolerated in unselected pts with previously-treated MPM. This study did not meet its primary endpoint. Additional strategies are necessary to develop novel immunotherapeutics and biomarkers of response in MPM. Clinical trial information: NCT03075527.
Mobile short message service (SMS) alerts for reducing the toxicity and improving protocol compliance during cancer chemotherapy: A randomized controlled trial.
Authors: Tanuj Chawla, Mohandas K. Mallath
Journal: Journal of Clinical Oncology (2019)

e18331 Background: Text message-based interventions has been used to facilitate patient care and enhance compliance in clinical oncology. This trial assessed the benefit of text message in reducing emergency room visits and other outcomes related to toxicity and expenses during cytotoxic chemotherapy. Methods: The study was funded by an International Innovation Grant from ASCO. This single center randomised controlled trial was done after approval from our Institutional Review Board. Briefly patients due to take 3-weekly chemotherapy for stomach/gastroesophageal cancer, colorectal cancer, breast cancer and lymphoma were enrolled. Randomization (1:1) was stratified by site and type of chemotherapy. Patients in standard care arm (STD) were given verbal and/or written instructions at the start of each chemotherapy cycle. The interventional (SMS) arm received periodic text messages in addition to the standard care on early warning signs of toxicity at regular intervals during each chemotherapy cycle. Participants were evaluated at the baseline and then followed up for 3 cycles (adjuvant setting) or 4 cycles (palliative setting). Primary endpoint was emergency room (ER) visits. Secondary endpoints included Suspected Unexpected Serious Adverse Reactions (SUSARs), delayed chemotherapy cycles, dose reductions, total cost of care and out of pocket expenditure. The study was designed with a sample size of 400 subjects with an interim analysis planned when 190 patients were randomized. Results: From May 2015 to June 2016, 191 patients were randomized and 189 completed the study [97 in SMS arm and 92 in STD arm]. The median age was 51 years (Range: 23-69) and male:female was 1:2. The relative risk (RR) for ER visit compared to STD arm was 1.09 (95% CI: 0.86-1.38; p = 0.46). The RR for SUSARs was 1.04 (95% CI: 0.99-1.09; p = 0.2); the RR for dose delay was 1.06 (95% CI: 0.9-1.26; p = 0.44) and the RR for dose reduction and 1.16 (95% CI: 1-1.33; p = 0.03). This study was closed prematurely for futility. Conclusions: Text (SMS) message-based patient education during cancer chemotherapy does not to reduce ER visits, SUSARs or cost of care. Clinical trial information: CTRI/2015/02/005491.
Influence of WNT and DNA damage response pathway alterations on outcomes in patients with unresectable metastatic colorectal cancer.
Authors: Sebastian Mondaca, Henry S Walch, Subhiksha Nandakumar, Walid K. Chatila, Jaclyn Frances Hechtman, Andrea Cercek, Luis A. Diaz, Francisco Sanchez-Vega, Nancy E. Kemeny, Neil Howard Segal, Zsofia Kinga Stadler, Anna M. Varghese, Efsevia Vakiani, Marc Ladanyi, Michael F. Berger, David B. Solit, Jinru Shia, Leonard B. Saltz, Nikolaus D Schultz, Rona Yaeger
Journal: Journal of Clinical Oncology (2019)

3585 Background: We assembled a large series of consecutive patients with unresectable metastatic colorectal cancer (mCRC) to identify genomic biomarkers of response and survival. Methods: Patients with unresectable mCRC treated at Memorial Sloan Kettering with genomic tumor profiling between 2014 and 2017 were included. Patients who underwent upfront metastasectomy or received neoadjuvant/conversion chemotherapy were excluded. Clinical information was retrieved from electronic medical records, and we evaluated associations between genomic profiles with progression free survival (PFS) on first-line chemotherapy and overall survival (OS). Categorical data were analyzed by Fisher exact test and time-to-event data were analyzed by Cox proportional hazards models. Results: Of 1453 mCRCs profiled in this period, 471 patients met the study criteria. Median age was 59 years (range, 18 to 95), and 73% of patients were stage IV at diagnosis. Most tumors (91%) were microsatellite stable (MSS). The most frequent first-line regimen was FOLFOX +/- bevacizumab (66%). Among MSS patients treated with oxaliplatin-containing regimens (n = 305), 7% harbored alterations in genes associated with DNA damage response (DDR) (BRCA1, BRCA2, ATM, PALB2). DDR gene alterations were not associated with PFS (P = 0.94) nor were different quartiles of large-state transitions (P = 0.54). Genomic alterations that significantly varied by duration of response included BRAF (16%, 10%, and 5% for PFS &lt; 6 months, 6-12 months, and &gt; 12 months, respectively) and APC (62%, 74%, and 80% for PFS &lt; 6 months, 6-12 months, and &gt; 12 months, respectively). APC mutation, single or dual, was associated with significantly longer PFS (HR 0.67) and OS (HR 0.59) in multivariate analysis versus no WNT pathway alteration or alterations in other WNT pathway genes (RNF43, AXIN2, CTNNB1). Conclusions: In unresectable mCRC patients, mutations in APC were associated with better outcomes; absence of an APC alteration or the occurrence of other WNT pathway alterations was associated with shorter survival. Somatic alterations in DDR genes were not associated with outcomes in mCRC patients receiving oxaliplatin-containing regimen.
“Good Risk”: low-risk patients with ductal carcinoma in situ (DCIS) benefit from whole breast radiotherapy after breast conservation surgery (BCS)–long-term follow-up.
Authors: Anna Niwinska, Jacek Galecki, Agnieszka Irena Jagiello-Gruszfeld, Wojciech Michalski
Journal: Journal of Clinical Oncology (2019)

e12062 Background: Identification of patients group with low risk DCIS that do not require radiation therapy after BCS is still a challenge. We assessed recurrence rates in patients with „good risk” DCIS with and without radiotherapy after BCS, and subsequently compared our results with the long-term data from RTOG 9804 trial [1]. Methods: Out of 737 patients with DCIS managed between 1996-2011 at the Cancer Center Warsaw, Poland, 400 were treated conservatively. Out of those 133 were classified as „good risk” patients in accordance with RTOG 9804 trial criteria (DCIS &lt; 2.5 cm, mammographically detected, NG1/G2 with margin = &gt; 3 mm). 79 patients received only BCS and another 54 patients were treated with BCS and radiotherapy. Competing risk of recurrence, DFS and OS were calculated for both groups. The results were compared with the long-term observation results of RTOG 9804 trial. Results: The competing risk of recurrence after 10 years in the group treated with BCS and in patients receiving BCS with radiotherapy was 26% and 6% respectively (p = 0.013). 10-year DFS was 58% and 88% (p = 0.02) and OS was 94% and 97% (p = 0.3) respectively. Based on the ASTRO Conference 2018, 10-year recurrence risk without and with radiotherapy in RTOG 9804 trial were 9.1% and 1.7% [1]. In our study in comparison to RTOG 9804 trial results, more patients had DCIS sized 1.1-2.5 cm, excision margins of 3-9 mm and no patient received adjuvant tamoxifen. Conclusions: Similarly to the results of RTOG 9804 trial [1], radiotherapy reduced recurrence rate in “good risk” DCIS, however, in our study the recurrence rate was higher - probably due to difference in risk factors and no tamoxifen use. 1.McCormick B et al. Randomized trial evaluating radiation following surgical excision for “Good Risk” DCIS: 12year report from NRG/RTOG 9804. ASTRO October 21, 2018.
Clinical importance of long noncoding RNA LINC00460 expression in plasma cell-free tumor RNA in <i>EGFR</i>-mutant adenocarcinoma.
Authors: Kazutoshi Isobe, Yuta Nakano, Hiroshi .Kobayashi, Kyohei Kaburaki, Go Sano, Susumu Sakamoto, Yujiro Takai, Naobumi Tochigi, Tetsuo Mikami, Akira Iyoda, Sakae Homma
Journal: Journal of Clinical Oncology (2019)

e20529 Background: Long noncoding RNA (lncRNA) is longer than 200 nucleotides and does not encode proteins. The IncRNA LINC00460 was reported to be involved in physiological and pathological processes such as proliferation, invasion, metastasis, and epithelial–mesenchymal transition (EMT). However, its role in epidermal growth factor receptor ( EGFR)-mutant lung adenocarcinoma is unclear. Methods: Non–small cell lung cancer (NSCLC) cells with knockout of LINC00460 were generated with a CRISPR-Cas9 system and used to investigate the effect of LINC00460 on gefitinib-induced cell death in an MTT assay. Western blot was used to observe change in EMT-related proteins, and changes in expression of EMT-related proteins were detected with an immunofluorescence assay. In addition, among 38 EGFR mutant lung adenocarcinomas treated by EGFR-TKI, cell-free tumor RNA extracted from blood plasma samples was analyzed for LINC00460 by using a real-time PCR assay. In addition, we assessed the association between LINC00460 expression and progression-free survival (PFS) after EGFR-TKI therapy. Results: LINC00460 was up-regulated by EGFR activation. LINC00460 expressions were significantly greater in NSCLC tumors than in adjacent normal tissues (p &lt; 0.01). H1299 cells with LINC00460 knockout were more sensitive to gefitinib. LINC00460 was induced by transcription factors such as FOS and NF-κB in EGFR-mutant lung adenocarcinoma and gefitinib-resistant cells. LINC00460 overexpression was involved in gefitinib resistance. The MTT assay showed that LINC00460 expression was greater in cells with acquired resistance to EGFR-TKIs (gefitinib, erlotinib, and osimertinib). Western blot and immunofluorescence revealed that LINC00460 expression was associated with changes in the expression of EMT-related proteins. Patients with high LINC00460 expression in plasma cell-free tumor RNA had significantly shorter PFS after EGFR-TKI therapy than did those with low expression (median PFS: 688 vs 1089 days, respectively; p = 0.024). Conclusions: LINC00460 appears to be a novel factor involved in malignant transformation of EGFR mutant–positive lung adenocarcinoma and increased EGFR-TKI resistance. LINC00460 expression in plasma cell-free tumor RNA in EGFR-mutant adenocarcinoma was associated with shorter PFS after EGFR-TKI therapy.
The "INSIGHT" Trial: Two new strata of an explorative, open-labeled phase I study evaluating the feasibility and safety of subcutaneous IMP321 injections (LAG-3Ig fusion protein, eftilagimod alpha) combined with either standard-of-care drug therapy or PD-L1 inhibition (avelumab) in advanced-stage solid tumor entities.
Authors: Daniel Wilhelm Mueller, Thorsten Oliver Goetze, Akin Atmaca, Mohammad-Reza Rafiyan, Eckhart Weidmann, Christian H. Brandts, Urs Pabst-Giger, Markus Duex, Thomas Werner Kraus, Simon Stahn, Regina Eickhoff, Salah-Eddin Al-Batran
Journal: Journal of Clinical Oncology (2019)

TPS2651 Background: The two new strata of the INSIGHT trial evaluate feasibility and safety of s.c. injections of IMP321 (eftilagimod alpha) in combination with either SOC first/second-line drug therapy (Stratum C) or in combination with an PD-L1 inhibitor (avelumab; Stratum D) in advanced stage solid tumors as well as to generate first efficacy data. This proof-of-concept data could build the basis for further clinical studies exploring the therapeutic potential of combinations of active immunotherapy using IMP321 with SOC drug therapies or immunotherapies targeting the PD-1/PD-L1 axis in various solid tumor entities. IMP321 is a MHC class II agonist that activates antigen-presenting cells (primary target cells) and then CD8 T cells (secondary target cells). Activation of the dendritic cell network and subsequent T cell recruitment at the tumor site with IMP321 may lead to enhanced anti-tumor CD8 T cell responses. Thus, especially combinations with PD-1/PD-L1 inhibitors might display interesting effects by activating immune cells and disabling immune inhibitory mechanisms at the same time. Methods: This is a prospective investigator initiated phase I trial consisting of four strata. New stratum C: Patients with solid tumors treated with SOC chemo- or targeted therapy in first or second line receive concomitant s.c. IMP321 injections. This combination is aimed to enhance the immune response against tumor cells compared to chemo-/targeted SOC therapy alone. New stratum D: Patients will receive avelumab i.v. q2w along with s.c. IMP321 injections. This combination is aimed to enhance efficacy by combining IMP321’s activating effects on immune cells with the release of immune inhibitory effects caused by interruption of the PD-1/PD-L1 axis. It is planned to enroll 20 patients in Stratum C and 12 patients in stratum D. Main efficacy endpoint is the overall response rate (RECIST 1.1). Overall recruitment has started; currently (Feb 2019) 14 patients have been enrolled. EudraCT: 2016-002309-20. Clinical trial information: NCT03252938.
Five-year analysis on the long-term effects of dabrafenib plus trametinib (D + T) in patients with <i>BRAF V600</i>–mutant unresectable or metastatic melanoma.
Authors: Paul D. Nathan, Caroline Robert, Jean Jacques Grob, Daniil Stroyakovskiy, Boguslawa Karaszewska, Axel Hauschild, Eugeny Levchenko, Vanna Chiarion Sileni, Jacob Schachter, Claus Garbe, Igor Bondarenko, Michael A. Davies, Antoni Ribas, Keith Flaherty, Paul Burgess, Monique Tan, Eduard Gasal, Dirk Schadendorf, Georgina V. Long
Journal: Journal of Clinical Oncology (2019)

9507 Background: First-line treatment with D+T demonstrated prolonged progression-free survival (PFS) and overall survival (OS) in patients with BRAF V600–mutant unresectable or metastatic melanoma. With 5 years of follow-up, we report survival and describe characteristics of patients in the phase 3 COMBI-d and COMBI-v trials with long-term benefit. Methods: Pooled 5-year landmark data for patients treated with D+T in the phase 3 COMBI-d (NCT01584648) and COMBI-v (NCT01597908) trials were analyzed. The trials enrolled patients with previously untreated BRAF V600E/K–mutant unresectable or metastatic melanoma. Patients received D 150 mg twice daily plus T 2 mg once daily vs either D + placebo (COMBI-d) or vemurafenib (COMBI-v). The primary endpoints were PFS in COMBI-d and OS in COMBI-v. Results: The pooled population included 563 patients who received D+T (COMBI-d, n = 211; COMBI-v, n = 352). Four- and 5-year PFS and OS rates were similar, suggesting a stabilization (4- and 5-year PFS, 21% [95% CI, 17%-24%] and 19% [95% CI, 15%-22%, respectively]; 4- and 5-year OS, 37% [95% CI, 33%-42%] and 34% [95% CI, 30%-38%], respectively). In patients with normal baseline lactate dehydrogenase (LDH) levels the 5-year PFS rate was 25% vs 8% in patients with elevated baseline LDH levels. Similarly, the 5-year OS rate was considerably higher in patients with normal baseline LDH levels vs those with elevated LDH levels at baseline (43% vs 16%). Among patients with normal baseline LDH levels and &lt; 3 organ sites with metastases, the 5-year PFS and OS rates were 31% and 55%, respectively. In addition, exploratory analyses will be performed to characterize subgroup(s) of patients most likely to experience long-term benefit. Of 299 patients who received subsequent anticancer therapy following treatment with D+T, 151 (51%) received an anti–CTLA-4 therapy and 102 (34%) received an anti–PD-1 therapy. The safety profile of D+T was as previously reported, and no new safety signals were observed. No treatment-related deaths were reported. Conclusions: First-line treatment with D+T leads to durable long-term benefit in many patients with BRAF V600–mutant unresectable or metastatic melanoma. Clinical trial information: NCT01584648; NCT01597908.
Treatment of advanced gastrointestinal cancer with genetically modified autologous mesenchymal stem cells: Final results of the phase 1/2 TREAT-ME-1 trial.
Authors: Jobst C. von Einem, Christine Guenther, Hans Dieter Volk, Gerald Gruetz, Daniela Hirsch, Christoph Salat, Oliver J Stoetzer, Peter J Nelson, Marlies Michl, Dominik Paul Modest, Julian Holch, Martin K Angele, Christiane J. Bruns, Hanno Niess, Volker Heinemann
Journal: Journal of Clinical Oncology (2019)

e14648 Background: TREAT-ME-1, a Phase 1/2 open-label, first-in-human, first-in-class trial, evaluated the safety, tolerability and efficacy of treatment with genetically modified autologous mesenchymal stromal cells (MSC),MSC_ apceth_101, in combination with ganciclovir in patients with advanced gastrointestinal adenocarcinoma. Methods: All patients (6 in Phase 1; 7 in Phase 2) received three treatment cycles of MSC_apceth_101 on Day 0, 7, and 14 followed by ganciclovir administration according to the manufacturer’s instructions for 48─72 hours after MSC_apceth_101 injection. Three patients were treated with a total dose of 1.5 x 10 6 cells/kg MSC_apceth_101 (DL1). Ten patients were treated with a total dose of 3.0 x 10 6 cells/kg MSC_apceth_101 (DL2). Immunological and inflammatory markers were assessed.Time to progression, overall survival was evaluated by RECISTwithin 56 days after administration of MSC_apceth_101 administration. Results: A total of 54 AEs occurred in 9/13 patients, thereof 18 AEs in three patients of DL1 and 36 AEs in six patients of DL2. Six AEs were CTC-AE grade 3, all other AEs were lower CTC-AE grades.Five SAEs emerged in two patients of DL1 and six SAEs in four patients of DL2. Eight patients achieved stable disease (change in target lesions of -2 to +28%). For all patients, the median time to progression was 1.9 months (95% CI: 1.3, 3.6 months). Median overall survival could not be estimated as 8/10 patients were still alive at the end of the study (one year) and therefore censored. Post-study observation of patients showed a median overall survival of 15.6 months (ranging from 2.2─27.0 months). Treatment with MSC_apceth_101 and ganciclovir did not induce a consistent increase or decrease in levels of any of the tumor markers analyzed. No clear trends in the immunological markers assessed were observed. Conclusions: MSC_apceth_101 in combination with ganciclovir was safe and tolerable in patients with advanced gastrointestinal adenocarcinoma, with preliminary signs of efficacy in terms of clinical stabilization of disease. Clinical trial information: NCT02008539.