tbuckley/cabot-search huggingface dataset:
First-in-human phase 1 study of DS-1062a in patients with advanced solid tumors.
Authors: Jacob M. Sands, Toshio Shimizu, Edward B. Garon, Jonathan Greenberg, Ferdinand M. Guevara, Rebecca Suk Heist, Fumiaki Kobayashi, Yutaka Noguchi, Daisuke Okajima, Naoyuki Tajima, Alexander I. Spira, Noboru Yamamoto, Aaron Elliott Lisberg
Journal: Journal of Clinical Oncology (2019)

9051 Background: DS-1062a is a trophoblast cell-surface antigen 2 (TROP2)-targeting antibody drug conjugate. TROP2 is highly expressed in epithelial cancers, including non-small cell lung cancer (NSCLC). Overexpression of TROP2 may be associated with poor survival in some solid tumors. Preclinical studies showed promising antitumor activity of DS-1062a in mouse models with TROP2-positive tumors. Preliminary results are reported in the dose escalation part of this phase 1 study. Methods: This is an ongoing phase 1 study of DS-1062a in patients (pts) with advanced solid tumors in the US and Japan (NCT03401385). Adult (age ≥20 years in Japan or ≥18 years in US) pts with measurable disease per RECIST v1.1 and sufficient tumor tissue sample for TROP2 measurement were eligible. Pts were excluded if they had multiple primary malignancies or untreated brain metastases. Endpoints included safety, pharmacokinetics, and efficacy. Results: As of November 16, 2018, 22 pts with advanced NSCLC were treated with DS-1062a at doses of 0.27-mg/kg (n = 4), 0.5-mg/kg (n = 5), 1.0-mg/kg (n = 7), and 2.0-mg/kg (n = 6). Overall, mean (standard deviation) treatment duration and cumulative dose were 7.8 (4.1) weeks and 181.8 (141.4) mg, respectively, with a median of 2 (range 1–6) cycles initiated. The majority (n = 18; 81.8%) of pts had ≥1 treatment-emergent adverse event (TEAE). The most common TEAE, fatigue (n = 9), was the only grade ≥3 treatment-related TEAE (n = 1; 2.0-mg/kg). Serious TEAEs, reported in 5 pts in the 0.27-mg/kg (n = 2), 0.5-mg/kg (n = 2), and 2.0-mg/kg (n = 1) cohorts, were not treatment-related. TEAEs leading to discontinuation occurred in 1 pt in the 0.27-mg/kg cohort (pleural effusion; not treatment-related). One pt died due to progressive disease. Peak concentration (C max ) and area under the curve from time 0 to last measurable concentration (AUC last ) increases were generally dose proportional. Of 18 tumor evaluable pts, 1 had a partial response (PR; 1.0-mg/kg), and 8 had stable disease (SD). Conclusions: DS-1062a was well tolerated at doses up to 2.0-mg/kg. An observable PR and multiple pts with SD warrant further evaluation of DS-1062a. The maximum tolerated dose has not been reached, and this study is ongoing. Clinical trial information: NCT03401385.
A large multicenter study evaluating prognosis and chemosensitivity of metastatic colorectal cancers with microsatellite instability.
Authors: David Tougeron, Benjamin Sueur, David Sefrioui, Lucie Gentilhomme, Thierry Lecomte, Thomas Aparicio, Gaetan DES Guetz, Pascal Artru, Christelle De La Fouchardiere, Valérie Moulin, Vincent Hautefeuille, Romain Coriat, Yann Touchefeu, Cedric Lecaille, Goujon Gael, Aurélie Ferru, Jean-Marc Tourani, Sheik Emambux, Julien Taieb, Aziz Zaanan
Journal: Journal of Clinical Oncology (2017)

3536 Background: Deficient Mismatch Repair (dMMR) in colorectal cancers (CRC) represent 12% of all tumors. In non-metastatic CRC setting, dMMR are associated with good prognosis but also with resistance to adjuvant 5-FU chemotherapy. In metastatic CRC (mCRC) setting, dMMR is found in less than 5% and its influence on prognosis and treatment response is little known. Methods: This multicenter retrospective study included all consecutive patients with dMMR mCRC treated between 2005 and 2015 in 17 centers. The Kaplan-Meier method was used to calculate overall survival (OS) and progression-free survival (PFS). Prognostic variables were evaluated in univariate analysis using the Log rank test and in multivariate analysis using the Cox regression model. Results: A total of 198 patients with dMMR mCRC were included (median age 64.6 years). dMMR mCRC were mostly diagnosed with synchronous metastases (59%) and frequent peritoneal carcinosis (43%). Lynch syndrome was found in 34% of cases and 36% of tumors had a BRAF V600E mutation. Median OS was 20.6 months. A low risk Kohne's prognostic index (HR = 0.40 [0.22-0.72], p = 0.02) and absence of peritoneal carcinosis (HR = 0.51 [0.29-0.90], p = 0.02) were associated with better OS in multivariate analysis. Main first-line regimens were 5FU-based (n = 20), oxaliplatin-based (n = 75) or irinotecan-based (n = 46) chemotherapy. Median PFS on first-line treatment was 5.9 months. The objective response rate (ORR) was 0%, 19% and 36% for 5FU-based, oxaliplatin-based and irinotecan-based chemotherapies, respectively (p = 0.02). A trend for a longer PFS (3.3, 5.5 and 10.2 months, respectively, p = 0.06) and OS (17.7, 21.1 and 34.2 months, respectively, p = 0.05) was also observed for irinotecan-based chemotherapy. The addition of bevacizumab to chemotherapy was associated with a significant increase of ORR (p = 0.01) and PFS (p = 0.04) as compared to the addition of an anti-EGFR therapy. Conclusions: This study suggests that dMMR mCRC are associated with poor prognosis and chemoresistance, especially to 5FU-based chemotherapy. Efficacy of irinotecan and bevacizumab should be evaluated in a prospective trial in combination with immune checkpoint inhibitors.
Clinical observation of yizhongshengxue capsule on the treatment of advanced gastric cancer-related anemia.
Authors: Li Hou, Jia Wang, Jing Wang, Ya Li, Xinyi Chen
Journal: Journal of Clinical Oncology (2017)

e21696 Background: Cancer-related anemia is an important factor that affects the clinical efficacy and quality of life for patients with advanced gastric cancer. This study is to observe the clinical efficacy of Yizhongshengxue Capsule, which is an herbal formula, on advanced gastric cancer-related anemia. Methods: A total of 96 eligible patients were randomized into three arms: 46 patients in the experimental arm, 26 patients in the positive control arm, and 24 patients in the negative control arm. All three arms received basic treatment of conventional medicine. Meanwhile, the experimental arm received Yizhongshengxue Capsule at the dosage of 3 capsules, 3 times daily. The positive control arm received Fufangejiao Syrup at the dosage of 20 ml, 3 times daily. The negative control arm received only basic treatment of western medicine. The course of treatment was 5 weeks. Results: After the 5-week-treatment, there was a statistically significant rise ( p&lt;0.05) of hemoglobin(HGB) in both experimental arm and positive control arm. The negative control arm had no statistically difference of HGB ( p&gt;0.05) before and after the treatment. Symptoms of dizziness, fatigue, loss of appetite, palpitation and insomnia in experimental arm were improved after the treatment ( p&lt;0.05). Symptoms of fatigue and loss of appetite in positive control arm were alleviated after the treatment ( p&lt;0.05). The negative control arm had no statistically difference in the above symptoms ( p&gt;0.05) before and after the treatment. Furthermore, there was a significant improvement of dizziness, loss of appetite, palpitation and insomnia in the experimental arm compared to the negative control arm ( p&lt;0.05). Finally, an improvement of the Karnofsky Performance Score(KPS) was seen only in the experimental arm after the treatment compared to that before the treatment ( p&lt;0.05). Conclusions: Our study shows that Yizhongshengxue Capsule can not only improve the clinical symptoms and quality of life in patients with advanced gastric cancer-related anemia, but also reduce or even reverse the trend of HGB decrease. Therefore, it is very promising in treating cancer-related anemia. Clinical trial information: ChiCTR-TRC-13003604.
Healthcare resource utilization (HRU) and costs associated with renal impairment (RI) among treated multiple myeloma (MM) patients.
Authors: Rohan Medhekar, Adrienne M. Gilligan, Shia T. Kent, Chaoling Feng, Caroline Henriques
Journal: Journal of Clinical Oncology (2018)

e18922 Background: RI is a common complication of MM leading to significant morbidity. Limited real-world data exist on economic burden of RI in MM patients. This study compared HRU and costs between treated MM patients with and without RI. Methods: In this retrospective analysis, adult patients treated for MM were identified from the MarketScan® data between 07/01/2006-12/31/2016. RI patients had at least one chronic kidney disease, end-stage renal disease, or dialysis claim on or after the first MM diagnosis (1st RI claim = index date) and were propensity score matched 1:1 to non-RI patients on demographic, baseline clinical variables and costs. Non-RI patients' index dates were based on the distribution of RI index dates. Patients had continuous enrollment for 12 months prior to and 3 months after index and were followed until earlier of inpatient death, end of data or enrollment. Average per patient per year (PPPY) all-cause HRU and costs (2016 dollars) were compared between RI and non-RI patients. Results: A total of 2,158 treated MM patients with RI were matched to treated non-RI patients. Matched patients were well balanced on the following criteria: age [mean 66.3 (standard deviation (SD) 11.3) and 66.6 [SD 11.5] years); gender (42.7% and 41.3% female); Charlson comorbidity index (mean 3.7 [SD 2.8] and 3.8 [SD 3.0]). Compared to non-RI patients, RI patients had significantly higher PPPY all-cause HRU, and inpatient, outpatient and total costs (Table 1). Table 1. Treated MM Patients All-cause HRU and costs PPPY, Mean (SD) Conclusions: Among propensity score-matched MM patients, RI has significant economic burden on patients with higher all-cause HRU and costs compared to non-RI patients. Supportive care for RI management and treatment with evidence-based antimyeloma therapy is crucial for these patients. RI Non-RI p-value All-cause HRU IP 1.8 (2.2) 1.0 (1.5) < 0.001 OP 131.8 (85.2) 100.4 (60.4) < 0.001 Pharmacy 57.2 (30.5) 54.9 (31.3) 0.018 All-cause costs IP $75,971 ($141,236) $38,542 ($92,011) < 0.001 OP $113,250 ($140,163) $85,445 ($91,689) < 0.001 Pharmacy $41,410 ($40,799) $48,423 ($47,967) < 0.001 Total $230,631 ($225,246) $172,410 ($152,196) < 0.001 IP inpatient; OP outpatient
Immune-related genes to predict clinical outcome of cetuximab (cet) treatment for metastatic colorectal cancer (mCRC): Immuno-Oncology assay research.
Authors: Yu Sunakawa, Eva Wang, Chris Roberts, Dongyun Yang, Qian Liu, Debrah Thompson, Ihab Botros, Miriana Moran, Stephanie H. Astrow, Jack Hsiang, Wu Zhang, Akihito Tsuji, Tadamichi Denda, Ken Shimada, Mitsugu Kochi, Masahiro Takeuchi, Masashi Fujii, Toshifusa Nakajima, Wataru Ichikawa, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2016)

11591 Background: CRC Subtyping Consortium identified 4 molecular subtypes, one of which was classified by factors including activation or expression of immune-related pathways (Guinney J, et al. Nat med 2015). The antitumor activity of cet requires antibody-dependent cell-mediated cytotoxicity (ADCC) driven by natural killer (NK) cells. Strategies to amplify the NK cell activation may improve the efficacy of cet (Kohrt HE, et al. J Clin Invest 2014), suggesting the ADCC activity may be affected by extracellular immune mechanisms. We therefore investigated whether immune-related genes will predict outcome in mCRC patients (pts) treated with cet. Methods: We measured expression levels of 354 immune-related genes implicated in the host immune response to tumors by HTG EdgeSeq Oncology Biomarker Panel, which comprises 2560 gene probes, using next generation sequencing for quantitative analysis of targeted RNAs. Total RNA isolated from tissues of 77 KRAS wild-type pts (57% males, median age of 63 years, 90% of performance status 0, and 15% right-colon cancer) enrolled in 2 phase II trials (JACCRO CC-05:UMIN000004197 or CC-06:UMIN000007022) of 1st-line therapy with FOLFOX or SOX plus cet was analyzed. Univariate Cox regression analysis was performed for all genes that passed QC filtering. Hierarchical clustering was performed using genes under 0.01 of the Cox p-value. Results: In progression-free survival, the clustering using 2 significant genes, RIPK1 and CEACAM5, could divide all participants into 2 groups and the Kaplan-Meier (KM) curve had a significant difference (mean 3.2 vs. 11.7 months, p= 7.61e-08). In overall survival (OS), 2 groups were classified based on the clustering using 7 genes and the KM curves were significantly different (mean 10.8 vs. 26.0 months, p= 5.79e-06). The Cox regression analysis revealed that IRF3 and BMP4 had strong associations with OS (p= 6.02×10-4, adjusted FDR.p= 0.043 and p= 8.69×10-4, FDR.p= 0.043, respectively). Conclusions: Our study demonstrates that immune-related genes may identify subtypes associated with clinical outcome of 1st-line cet treatment for mCRC. Further studies to validate the findings are warranted.
Sequence of stereotactic ablative radiotherapy and immune checkpoint blockade in the treatment of metastatic lung cancer.
Authors: Ramya Pinnamaneni, Aparna Madhukeshwar Hegde, Sulochana Devi Cherukuri, Hyder Husain Arastu, Mark Bowling, Clinton Leinweber, Chipman Robert Geoffrey Stroud, Cynthia R. Cherry, Paul R. Walker
Journal: Journal of Clinical Oncology (2017)

e20665 Background: Monoclonal antibodies targeting immune checkpoint proteins have recently been shown to elicit robust and durable responses in patients with advanced lung cancer. However, with response rates ranging from 15-20%, immunomodulatory strategies are needed to improve outcomes. Stereotactic ablative radiotherapy (SABR) may be a promising immunomodulatory strategy given its synergistic effects without added toxicity. Several pre-clinical trials combining SABR and immunotherapy have shown improvement in progression free and overall survival. Given this, it has been our multidisciplinary programmatic approach to bring in SABR in patients receiving immunotherapy for a potential immune boost. Methods: This is a retrospective study evaluating the overall survival (OS) of all lung cancer patients who received Nivolumab with SABR at our institution. We included lung cancer patients of all pathologic subtypes who received Nivolumab. We identified patients who received SABR, to sites of symptomatic metastatic disease, within 30 days preceding (Before) or during (Sandwich) Nivolumab treatment. Results: Out of 76 lung cancer patients treated with Nivolumab, 22 received RT- 10 Before and 12 Sandwich. At a median follow up time of 10.6 months (mo), median OS for patients with no RT was 4.8 mo, Before was 5.2 mo and Sandwich was not reached (NR) (p = 0.06). The 1 year OS for the Sandwich arm was 52.1%. When compared to no RT, the Before arm had a statistically insignificant reduction in mortality (HR 0.59, 95% CI 0.25 – 1.41, p = 0.24). The Sandwich arm had a statistically significant reduction in mortality (HR 0.37, 95% CI 0.14 – 0.94, p = 0.04). Conclusions: There is an improvement in OS when SABR is administered as a Sandwich approach during Nivolumab treatment, likely due to SABR-induced neoantigen release, increased PDL1 expression and subsequent abscopal effect. Further prospective studies are needed to evaluate optimal sequencing, dose and site of RT with immunotherapy. [Table: see text]
Next-generation-sequencing of advanced melanoma: Which genetic alterations have an impact on systemic therapy response?
Authors: Andrea Forschner, Franz J. Hilke, Tobias Sinnberg, Heike Niessner, Thomas K. Eigentler, Claus Garbe, Olaf Riess, Stephan Ossowski, Tobias Haack, Christopher Schroeder
Journal: Journal of Clinical Oncology (2018)

e21557 Background: Next-generation sequencing will gain more and more importance for melanoma patients. Detection of genetic alterations in tumor tissue may help to understand mechanisms of resistance to immunotherapy or targeted therapy. Taking those resistance mechanisms into account from the outset of disease, it would be easier to choose the “individual” best treatment option, especially in patients with an existing BRAFV600 mutation. Methods: Since March 2017, we have routinely performed NGS diagnostics (including ≥ 336 genes) in tumors of advanced melanoma patients with limited treatment options. The first 50 deeply (300-500x) sequenced tumor samples of 50 different patients have now been evaluated. We matched the sequencing results with clinical data to determine whether there are any risk factors associated with treatment failure, such as combined treatment with ipilimumab and nivolumab. Results: 29 men and 22 women were included, median age was 61 years (IQR 49-75). The different melanoma types were: mucosal melanoma (MM) (n = 7), acral lentiginous melanoma (ALM) (n = 6), uveal melanoma (UM) (n = 6), other melanoma of the skin (n = 32). 21/32 (66%) of the patients had progressive disease under combined therapy with ipilimumab and nivolumab for metastases. Median mutational load was 5.6 variants / Mbp. The lowest mutational load was found in the subgroups of MM, ALM and UM. Interestingly we found more frequently copy number variants (CNVs) and single nucleotide variants (SNVs) in these subgroups. We outline the most frequent CNVs and SNVs and work out in particular what changes have been found in the area of cell cycle regulation and DNA damage response. In this setting we show that certain deletions and/or amplifications are more common in immunotherapy-resistant patients. Conclusions: Our analysis demonstrates the importance of NGS in advanced melanoma patients. The results may help to understand resistance mechanisms and therefore to find the best treatment option to start. Furthermore, new therapeutic options such as targeted drugs might be available for patients suffering resistance to established treatments. In this context, molecular tumor boards have a great importance.
Comparison of neoadjuvant anti-HER2 therapy for breast cancer in public versus private health care: Time to shorten the distance.
Authors: Virginia Braga, Jessica Ribeiro Gomes, Noelle Suemi Wassano, Jessica Sayuri Tsukamoto, Luiza Damian Ribeiro Barbosa, Diocesio Alves Pinto de Andrade, Marcelo Rocha De Sousa Cruz
Journal: Journal of Clinical Oncology (2017)

e18045 Background: In the neoadjuvant setting (NAC) of HER2-positive breast cancer (BC), the addition of pertuzumab (P) to trastuzumab (T) and chemotherapy (chemo) has increased pathological complete response (pCR) from 40-50% to over 70%. Recent data has shown that pCR is a reliable surrogate marker of disease-free (DFS) and overall survival (OS). In Brazil, there is an important gap between cancer drugs approved in the public health care system (PHCS) vs. the private setting. Although P approval for NAC (Aug/2016) and metastatic setting (Sep/2015) in the private health system, it is not approved for any indication in the PHCS. Likewise, T is not approved for use as NAC at the PHCS. We aim to compare private practice experience of T + P + chemo in the NAC vs. HER2-positive advanced BC patients treated at the PHCS. Methods: Retrospective analysis of 95 patients diagnosed with locally advanced HER2-positive BC by immunohistochemistry 3+ or FISH according to ASCO/CAP definition. We evaluated 17 consecutive patients at the COAEM private cancer center in Brazil since Feb/2014 (cohort 1). Neoadjuvant therapy was T and P plus docetaxel-based chemo. A cohort of 78 patients with locally advanced HER2-positive BC treated in a PHCS cancer center was analyzed (cohort 2). They received standard NAC regimen according to PHCS guidance: anthracycline and taxane-based therapy without anti-HER2 therapy. Results: Cohort 1: 17 patients with median age of 50 years (range 34-70); Four patients had clinical stage IIA; 2 patients IIB; 7 patients IIIA; 3 patients IIIB; one patient IIIC. The pCR rate was 70.5% (12 patients). Cohort 2: 78 patients with median age of 48 years (range 26-79). One patient IIB; 33 patients IIIA; 37 patients IIIB; 7 patients IIIC. The pCR rate was 16.7% (13 patients); 29 patients (37.2%) had clinical complete response. Only 26 patients (33.3%) received T in the adjuvant setting. Conclusions: Neoadjuvant P and T combined with chemo has shown pCR rates superior to 70% in clinical trials, which is a surrogate marker for DFS and OS in HER2-positive BC. The absence of anti-HER2 therapy in the PHCS must be urgently reviewed not just in light of double-blockage strategy but also in T monotherapy use.
Value-Based Payments and Inaccurate Risk Adjustment—Who Is Harmed?
Authors: Julie Bynum, Valerie Lewis
Journal: JAMA Internal Medicine (2018)

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Risk factors for central neck lymph node metastases in papillary thyroid microcarcinoma.
Authors: Weihui Zheng, Jinbiao Shang
Journal: Journal of Clinical Oncology (2017)

e17583 Background: Papillary thyroid microcarcinoma (PTMC) accounts for nearly half of all cases of thyroid papillary cancer. Although PTMC has a good prognosis, lymph node metastasis, especially central lymph node metastasis (CLNM), is the leading cause of local recurrence. The value of central lymph node dissection in PTMC remains controversial. Few studies have focused on the relationship between CLNM and multifocality in PTMC. This retrospective study of a large cohort of patients with PTMC aimed to identify assess the predictive value of multifocality for identifying patients at high risk of CLNM who may benefit from central lymph node dissection. Methods: Patients with PTMC who underwent total or hemi-thyroidectomy with effective unilateral or bilateral central lymph node dissection at Zhejiang Caner Hospital between January 2007 and December 2015 were enrolled ( n = 3543). Number and laterality of PTMC foci, extrathyroidal extension (ETE), tumor size, age, sex, positive/total number of central lymph nodes and other clinicopathological factors were recorded. The chi-square test was used for univariate analysis; logistic regression, for multivariate analysis. Results: Multifocality, age, sex, tumor size, ETE and nodular goiter were significantly associated with central lymph node metastasis (CLNM) in univariate analysis. Multifocality was an independent predictive factor for CLNM in multivariate analysis. Compared to unifocal disease, the odds ratio (OR) for CLNM was 1.447 for patients with ¡Ý 2 tumor foci ( P &lt; 0.001) and 2.978 for patients with ¡Ý 3 tumor foci ( P &lt; 0.001). Conclusions: Multifocality with ¡Ý 3 tumor foci was an independent predictive factor for CLNM in PTMC. Multifocality should be assessed when selecting patients for prophylactic central neck lymph node dissection, and we recommend patients with multifocality should undergo more radical treatment.