tbuckley/cabot-search huggingface dataset:
Targeting tumors and financial toxicity in AYAs: Exceptional response to dual immunotherapy in an uninsured young adult with soft tissue sarcoma.
Authors: Hal E. Crosswell, Jeremy Kilburn, Melissa Peters, Theresa Sandifer, James D. Bearden, Robert D. Siegel
Journal: Journal of Clinical Oncology (2018)

e23530 Background: Rising healthcare costs and patient financial toxicities are a pressing issue for the 70,000 AYAs diagnosed annually in the US. To address both of these issues, Bon Secours St. Francis (BSSF) implemented a comprehensive patient assistance program (CPAP) which focuses on providing copay assistance and/or free drug to qualifying patients. Because AYAs have the highest rate of underinsured or no insurance, we hypothesized that the CPAP would significantly benefit the AYA population and may provide direct survival benefit to patients who receive therapy as a result of this program. Methods: We describe the LEAN Six Sigma process of developing the CPAP, compare AYA versus non AYA access of the program and an exceptional responder of an AYA sarcoma patient to immunotherapy made feasible through the institutional CPAP. Results: A LEAN process was carried out and the CPAP was implemented in 2017. The CPAP consist of 1) free drug drug recovery and 2) copay assistance. These components utilize external resources such as drug manufacturers and foundations to aid in offsetting the high out-of-pocket expenses for chemotherapy. With internalizing the CPAP, BSSF more than doubled cost savings in FY2017, $738,450 versus FY2016, $308,038. The AYA population utilized the free drug recovery portion disproportionately more than non-AYA likely due to the fact that AYA patients have a higher rate of no insurance than adult counterparts. A 26 yo with metastatic alveolar soft parts sarcoma, refractory to multiple first and second line therapies was able to get dual immunotherapy with nivolumab and ipilumumab via the CPAP, and had a near complete response after just two cycles. Conclusions: The CPAP reduces institution and patient financial toxicity, a significant concern for the majority of AYAs. A CPAP may be indispensable for institutions developing AYA Programs. Our anecdotal case report of an exceptional responder to dual immunotherapy enabled by the CPAP suggests that the program may have direct patient benefit. Further multi-center, prospective studies are required to demonstrate survival benefit of a CPAP for AYAs.
Adjuvant cancer peptide vaccine for pathological node-positive esophageal SCC patients who underwent preoperative therapy followed by R0 resection.
Authors: Takushi Yasuda, Kohei Nishiki, Koji Yoshida, Osamu Shiraishi, Mitsuru Iwama, Hiroaki Kato, Yumiko Tanaka, Atsushi Yasuda, Masayuki Shinkai, Yasutaka Chiba, Kiyotaka Okuno, Yusuke Nakamura
Journal: Journal of Clinical Oncology (2016)

3087 Background: Three HLA-A-24-restricted epitope peptides have been identified, which were derived from three cancer-testis antigens that are expressed only in esophageal squamous cell carcinoma (ESCC) cell lines: up-regulated lung cancer 10 (URLC10), cell division cycle associated 1 (CDCA1) and KH domain-containing protein overexpressed in cancer 1 (KOC1). This was an exploratory, prospective, phase II study in a single institute to elucidate the efficacy of an adjuvant vaccine using these three kinds of epitope peptides. Methods: Patients with ESCC who underwent R0 resection after preoperative chemotherapy or chemoradiotherapy (CRT) from December 2009 to September 2014 and had pathological positive nodes were enrolled. A peptide vaccine (each with 1 mg of epitope peptides and 1 ml of Montanide ISA 51 VG) were administered 10 times weekly and then 10 times biweekly only in patients with HLA-A2402. No other adjuvant therapy was given until recurrence occurred. We evaluated relapse-free survival (RFS) as the primary endpoint and overall survival (OS) as the secondary endpoint. Results: Thirty-four patients were enrolled in the vaccine group (VG) and 30 were in the control group (CG). There was no significant difference in sex, age, tumor location and pTNM stage between the two groups. The median duration of follow-up of censored patients was 42 months (range, 11–72). Recurrence rate was 17/34 (50.0%) in the VG, 4 of whom are now cancer-free after surgery or CRT, resulting in 13 (38.2%) with recurrence under treatment. On the other hand, recurrence was observed in 19/30 (63.3%) in the CG, all of whom already died or are under treatment. Five-year RFS rate of the VG vs. the CG was 44.7% vs. 33.9% (p = 0.212) and 5-year OS rates were 62.3% vs. 31.0% (p = 0.027), respectively. Patients with pN2-3 in the VG and CG had a 5-year RFS rate of 30.3% vs. 15.6% (p = 0.152) and OS rate of 48.8% vs. 19.9% (p = 0.027). Conclusions: Our study findings suggest that the cancer peptide vaccine suppresses postoperative recurrence and improves the survival of patients with ESCC. A randomized, multicenter, phase III study is underway to clarify the efficacy of these peptide vaccines as adjuvant therapy for ESCC. Clinical trial information: UMIN000003557.
A phase I study of neoadjuvant cisplatin (C), docetaxel (D) and nintedanib (N) for resectable non-small cell lung cancer (NSCLC).
Authors: Tina Cascone, Boris Sepesi, Heather Y. Lin, Neda Kalhor, Jianjun Zhang, Frank V. Fossella, Anne S. Tsao, Vincent K. Lam, Charles Lu, Frank Mott, George R. Simon, Mara Antonoff, Reza J. Mehran, David C. Rice, Ara A. Vaporciyan, Myrna Godoy, J. Jack Lee, Stephen Swisher, William Nassib William, John Heymach
Journal: Journal of Clinical Oncology (2018)

8555 Background: Major pathologic response (mPR) in resected NSCLC following neoadjuvant chemotherapy correlates with long-term survival. This phase 1 study assessed the safety and efficacy of N added to neoadjuvant C and D, using mPR as primary surrogate of efficacy endpoint. Methods: Eligible patients (pts) had stage IB (≥4 cm) to IIIA (single station N2) resectable NSCLC (AJCC 7th). The study included an expansion phase of N 200 mg p.o. bid priming monotherapy for 28 days, followed by 3 cycles of C 75 mg/m2, D 75 mg/m2 every 21 days, and N 200 mg p.o. bid, and surgery (after a run-in phase in 6 pts determined safety of escalating N doses). With 33 pts, the study had 90% power to detect an increase in mPR from 15% (historical controls) to 35%, with a 10% type I error rate. Based on the Simon’s two-stage design, the protocol called for discontinuation of the trial if there were < 4 responders in the first 19 pts treated at N 200 dose level (NCT02225405). Results: From July 2015 to May 2017, 21 pts (15 female, 1/8/12 stages I/II/III) were treated (6 with N 150 mg bid, 15 with N 200 mg bid). Only 1/15 pts treated with N 200 mg bid achieved a mPR (6.7%, 95% CI 0.2% - 32.0%). An interim analysis demonstrated that the probability of observing ≥4 mPRs if accrual were to continue to 19 pts was only 5.4%, assuming the prior of p beta(0.35, 0.65). Hence, the study was discontinued for futility. The best objective response rate by RECIST 1.1 in all 21 pts was 33.3%. No patients responded to N priming monotherapy. With a median follow up time of 11 months, the 12-month RFS in the whole cohort was 71% (95% CI 49%, 100%). The most frequent treatment-related grade 3-4 toxicities in all pts were: transaminitis (14.3%); nausea (9.5%) and electrolyte abnormalities (14.3%). No unexpected perioperative complications were observed. Conclusions: Although tolerable, neoadjuvant N, C, and D did not increase the mPR rate compared to historical controls of induction chemotherapy alone. Additional studies of the combination in this setting are not recommended. Our trial design, utilizing mPR as an intermediary endpoint, may serve as a framework to rapidly screen novel compounds that should be investigated further as neoadjuvant therapies for resectable NSCLC. Clinical trial information: NCT02225405.
Whole exome analysis of patients (pts) with metastatic GIST (mGIST) demonstrating exceptional survival with imatinib (IM) therapy compared to those with short term benefit.
Authors: Eytan Ben Ami, Sophia C. Kamran, Suzanne George, Jeffrey A. Morgan, Andrew J. Wagner, Priscilla Merriam, Katherine Anne Thornton, Julia Jennings, Julie Field, Sarah Solomon, Chandrajit P. Raut, Eliezer Mendel Van Allen, George D. Demetri
Journal: Journal of Clinical Oncology (2017)

11513 Background: Most patients with mGIST initially benefit from IM therapy with durable disease control (DC), i.e. objective responses and stable disease, with median duration of approximately two years. We reported exceptional long-term benefit (LTB) with DC and overall survival (OS) &gt;14 years in a subset of mGIST pts treated with IM. We aimed to characterize tumor and normal genomes of exceptional LTB pts treated with IM and compare with short-term benefit (STB) pts. Methods: Among 87 mGIST pts enrolled between July 2000 and June 2001 in the B2222 trial of IM and followed prospectively at the Dana Farber Cancer Institute, we identified 10 LTB (&gt;14 years of DC) pts, and 6 STB (&lt;2 years of DC) pts on IM. Targeted genotyping ( KIT/PDGFRA)was performed in all tumors (n=16). Whole exome sequencing (WES) was performed on archival FFPE tumor samples from LTB and STB pts prior to any IM treatment. We compared WES results from LTB with STB pts to identify unique features of long-term DC and OS with IM. Results: KIT mutation in LTB pts were as follows: exon 11(6 pts), exon 9 (3 pts), and SDH-deficient with KIT/PDGFRA wild type (1 pt). In STB pts, mutated KITwas found 4 pts (exon 11) and 2 pts (exon 9). WES was successful in six LTB (five exon 11, one exon 9) and three STB (two exon 11, one exon 9) pts. A total of 1211 somatic mutations were observed (546 missense, 37 nonsense, 256 silent, 285 indels, 36 splice mutations). The mean somatic mutational burden was 3.42 mutations/Mb (range 1.18-4.93) and 3.34 mutations/Mb (range 1.06-6.68) among LTB and STB, respectively. Genes mutated in LTB but not in STB were MUC7 (4 pts), H1F0 (3 pts), ZKSCAN1 (3 pts), SLC24A1 (3 pts) and USP4 (2 pts). Conclusions: KRAB domain containing zinc finger (KRAB-ZNF) gene expression signatures have been associated with prediction of response to IM, and a possible role in response modulation to tyrosine kinase inhibitors in GIST. We found variants in ZKSCAN1, a gene encoding a transcriptional regulator of the KRAB subfamily of zinc finger, to be present in LTB but not in STB. KRAB-ZNF family of genes may be linked to LTB and exceptional survival with IM in mGIST; functional analyses will be important to test such hypotheses.
A phase II, open-label, multi-arm study of novel combinations of immunotherapies or DDR inhibitors in platinum-refractory, extensive disease small-cell lung cancer (ED-SCLC): BALTIC.
Authors: Joachim Von Pawel, Ihor Vynnychenko, Haiyi Jiang, Yifan Huang, Phillip A. Dennis
Journal: Journal of Clinical Oncology (2017)

TPS8585 Background: The prognosis of platinum-refractory ED-SCLC is poor, with ~95% of pts failing to respond to topotecan, the only approved 2 nd line treatment. SCLC is associated with a high mutation load and genomic instability, and data suggest that enhanced DNA repair could be a resistance mechanism. As such, immunotherapies and DNA damage repair inhibitors may be beneficial in this disease setting. Durvalumab (D) is a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab (T) is a selective human IgG2 mAb against CTLA-4. In a Phase 1b study in NSCLC (NCT02000947), D + T showed encouraging activity and manageable tolerability. AZD1775 is a small-molecule inhibitor of the DNA damage checkpoint kinase WEE1 that potentiates genotoxic chemotherapies and is being developed for the treatment of advanced solid tumors with genetic deficiencies in DNA repair mechanisms. In a Phase 2 study in platinum-refractory p53 mutated ovarian cancer (NCT01164995), AZD1775 + carboplatin showed promising activity and an acceptable safety profile. Methods: BALTIC (NCT02937818) is a Phase 2, open-label, multicenter, multi-arm, exploratory, signal-searching study to assess the preliminary activity of novel treatment combinations in refractory ED-SCLC. Eligible pts will have progressed during, or within 90 days of completing 1 st line platinum-based chemotherapy, and have life expectancy ≥8 wks. Each arm is independent and will open sequentially to enroll up to 20 pts. The study will open initially with 2 arms: D 1500 mg + T 75 mg i.v. q4w for 4 doses, followed by D monotherapy 1500 mg i.v. q4w (Arm A); and oral AZD1775 225 mg bid for 2.5 days from Day 1 + carboplatin AUC 5 on Day 1 i.v. q3w (Arm B). Pts will receive treatment until confirmed disease progression or discontinuation. Further arms may be added to assess other combinations once safe and tolerable doses and schedules have been established. The primary endpoint is investigator-assessed ORR (RECIST v1.1). Secondary endpoints include duration of response, disease control rate, time to response, PFS, OS, PK, safety and tolerability. Recruitment is ongoing. Clinical trial information: NCT02937818.
Efficacy, maximal tolerated dose, and toxicokinetics of TTC-352 in rats and dogs, a partial ER agonist for metastatic ER+ breast cancer.
Authors: Debra A. Tonetti, Rui Xiong, Jiong Zhao, Lauren Gutgesell, Arkadiusz Z. Dudek, Gregory R. Thatcher
Journal: Journal of Clinical Oncology (2017)

e14090 Background: The high prevalence of treatment resistance for estrogen receptor positive (ER+) breast cancer cause more deaths than all other breast cancers, despite the availability of endocrine therapeutics including selective ER downregulators (SERDs). Before tamoxifen, high dose estradiol (E2) delivered clinical efficacy slightly superior to tamoxifen. While recent clinical trials have shown efficacy of low dose E2, unacceptable side effects including vaginal bleeding, endometrial hypertrophy, and the negative perceptions of both patients and physicians limit acceptance. In preclinical models, tamoxifen resistant (TR) breast cancer is sensitive to treatment by E2. TTC-352 is an orally bioavailable selective human ERα partial agonist (ShERPA) designed to mimic E2 in causing tumor regression of TR breast cancer xenografts without uterine proliferation caused by E2 and tamoxifen. Methods: The published preclinical efficacy studies were extended to multiple TR ER+ cell lines in 3D spheroid cell cultures comparing to E2 and the SERD GDC0810. The maximum tolerated dose (MTD) was determined in Sprague-Dawley rats at: 200, 300, 600, 1000 and 2000 mg/kg by oral gavage (N = 3). Animals were observed for 7 days prior to necropsy. A single MTD range finding study was performed in dogs at: 50, 100, and 200 mg/kg TTC-352, administered orally in gelatin capsules. Based on these results, a 7-day repeated dose studies were completed at 30, 100, 300 and 1000 mg/kg/day in rats (3/sex/dose) and 15, 75, and 150 mg/kg (2/sex/dose) in dogs. Results: Growth of three TR ER+ breast cancer cell cultures in 3D was inhibited by TTC-352, which mimicked E2 and was equivalent to GDC0810. In female rats MTD was 1000 mg/kg and TTC-352 was well tolerated following a single oral dose of 200, 300, 600 mg/kg. The oral administration of TTC-352 at doses of 30, 100, and 300 mg/kg/day in rats (both sexes) and 15, 75 or 150 mg/kg/day in dogs (both sexes) for seven days was generally well tolerated. Conclusions: TTC-352 has demonstrated efficacy in preclinical models of TR breast cancer. Completed rat and dog studies indicated favorable tolerability and rapid absorption up to 300 mg/kg/day in rats and 150 mg/kg/day in dogs.
Association of self-reported physical activity with survival among patients with advanced non-small cell lung cancer (NSCLC).
Authors: Jimmy Ruiz, Antonius Arthur Miller, Janet Tooze, William J. Petty, Ajeet Gajra, Heidi D. Klepin
Journal: Journal of Clinical Oncology (2016)

e20664 Background: Patient assessment strategies are needed to individualize treatment planning for adults receiving palliative chemotherapy for NSCLC. We evaluated the utility of a cancer-specific geriatric assessment (GA) and Fried Frailty Index (FFI) to predict overall survival (OS). Methods: We conducted a multi-site pilot study of 50 patients (2010-14) with newly diagnosed metastatic NSCLC, age ≥ 18 years with no prior palliative chemotherapy. All subjects received carboplatin AUC 6, paclitaxel 200mg/m2every 3 weeks as initial therapy. GA and FFI were administered prior to chemotherapy. The GA includes: functional status (activities of daily living [ADLs], instrumental ADLs, Karnofsky performance status (KPS), Timed Up and Go (TUG), falls), self-reported comorbidity, Blessed-Orientation-Memory-Cognition (BOMC) test, social functioning and support, nutrition (weight loss, body mass index[BMI]), and polypharmacy. The FFI includes: weight loss, self-reported exhaustion, reported physical activity (frailty < 383Kcals/week men; < 270 Kcals/week women), walking speed, and grip strength. OS was measured from chemotherapy initiation using the Kaplan-Meier method. Cox proportional hazards models were fit to estimate the association between baseline patient characteristics and OS. Results: 48 subjects received chemotherapy and evaluable. The mean age was 68.5 y (range 42-86), 79% male, 85% KPS ≥ 80, mean hemoglobin 13.1±1.6. The median OS was 8 months. GA detected heterogeneity of baseline characteristics in multiple measures [mean (range)] including: IADL score 13.2 (7-14), TUG 11.4 seconds (5-22), comorbidities 2.4 (0-7), BOMC 3.6 (0-25), medications 5.9 (0-14), and BMI 26 (17-37.6). 27% met FFI criteria for frailty with ≥ 3 impairments. In multivariate analyses KPS ≤ 80 (Hazard ratio[HR] 3.6, 95% Confidence Interval [CI] 1.4, 9.3), hemoglobin (HR 1.3, 95% CI 1.1, 1.6) and low physical activity (HR 2.2, CI 95% 1.2, 4.3) were independently associated with shorter survival. Conclusions: Self-reported physical activity is associated with poor survival in this cohort and warrants further study as a marker of frailty among adults with advanced stage NSCLC. Clinical trial information: NCT01026467.
A prospective survey of comprehensive score for financial toxicity (COST) in Japanese cancer patients.
Authors: Kazunori Honda, Bishal Gyawali, Masashi Ando, Kyoko Kato, Yuki Kojima, Seiichiro Mitani, Toshiki Masuishi, Yukiya Narita, Hiroya Taniguchi, Shigenori Kadowaki, Takashi Ura, Kei Muro
Journal: Journal of Clinical Oncology (2018)

e22128 Background: Financial toxicity (FT) has negative impact on quality of life and survival of patients with cancer. COST is a well validated tool to measure FT in US. However, FT using COST questionnaire has not been well-studied for cancer patients in Japan where universal public health insurance system exists. Methods: This is a prospective survey to evaluate FT in advanced cancer patients. Eligible patients were receiving chemotherapy for solid tumors for at least 2 months. FT was measured using COST questionnaire translated into Japanese using FACIT methodology. COST questionnaire includes 11 items assessing patent-reported outcomes (score range 0?44). Based on these scores, FT have been subdivided into 4 grades, 26-44 (Grade0), 14-25 (Grade1), 1-13 (Grade2) and 0 (Grade3). Results: Of the 191 patients approached, 156 (82%) responded the questionnaire. Patient characteristics were as follows: median age (range), 67 (30-87); sex M/F, 83/73 (53/47%); primary site, colorectal/gastric/esophageal/thyroid/head and neck/other, 77/39/16/9/4/11 (49/25/10/6/3/7%). The median COST score was 21 (range, 0-41; mean±SD, 12.1±8.45). 106 patients (68%) suffered more than grade 1 FT. 42 (28%) patients cut spending on food or clothing, 67 (44%) on leisure and 95 (63%) used their savings to pay for cancer treatment. On multivariate analysis using linear regression, elder age (one year, correlation coefficient 0.15, 95% CI 0.02?0.28, P = 0.02) and higher household saving (over 15 million yen, 8.24, 95% CI 4.06?12.42, P = 0.0002) was significantly associated with higher COST score (lower FT). Non-regular employees (-5.37, 95% CI -10.16 ? -0.57, P = 0.03), retired because of cancer (-5.42, 95% CI -8.62 ? -1.37, P = 0.009) and using strategies to cope with the cost of cancer care expenses (-5.09, 95% CI -7.87 ? -2.30, P = 0.0004) were significantly associated with lower COST score. Conclusions: The COST questionnaire can be used for measuring FT in Japan where universal healthcare system and public ceiling amount for high-cost medical expense exist. Despite these provisions, some Japanese patients experienced meaningful FT during chemotherapy. Clinical trial information: 000025043.
Circulating cell-free DNA profiling for potentially actionable targets in metastatic castration resistant prostate cancer (mCRPC) using next-generation sequencing on droplet volumes of plasma.
Authors: Gurudatta Naik, Chen-Hsiung Yeh, Andrew Ford, Jonathan Spurgin, Christa Lidikay, Mike Mullen, Guru Sonpavde
Journal: Journal of Clinical Oncology (2016)

e16579 Background: Current methods to extract DNA from plasma are limited by the harvesting of small quantities of poor quality DNA. Circulogene Theranostics has developed a CLIA-certified proprietary method enabling the recovery of necrosis and apoptosis-associated, cell-free (cf)-DNA, with a high-yield ( > 300 ng/ml) of sequencing quality DNA from a drop of plasma. We report cfDNA sequencing data from mCRPC patients (pts) using this novel methodology. Methods: Pts with mCRPC underwent prospective blood collection at UAB. Twenty microliters of plasma collected in a microtainer EDTA tube was used for the harvesting of cfDNA. An automated workstation that can process up to 96 samples facilitates consistent and reliable studies with a turnaround time of 7-10 days. DNA is subjected to targeted ultra-deep (2,000X – 15,000X) Next Generation Sequencing (NGS) on the Ion Torrent platform to detect approximately 3000 hotspot mutations in 50 potentially actionable genes. Germline and unconfirmed/silent somatic mutations and mutations with allele frequency < 1% are filtered out based on dbSNP, 1000 genomes and COSMIC. Results: Plasma samples were available from 27 patients with mCRPC. A median of 840 ng (range 280-1640) of DNA was recovered from 20 µL of plasma per patient. The most common mutation at baseline was in the P53 gene, seen in 7 pts (25.9%), followed by KIT in 3 pts (11.1%) and VEGFR2 in 2 pts (7.4%). Mutations seen in 1 patient each (3.7%) were ALK, CTNNB1, EGFR, ERBB4, FGFR3, HNF1A, HRAS, IDH1, JAK3, KRAS, NOTCH1, PIK3CA, PTEN, PTPN11, RET, SMAD4 and VHL. Activating mutations were seen in ALK, HRAS, IDH1, JAK3 and VEGFR2, and inactivating mutations were seen in P53, PTEN and VHL. The dataset is expanding and results will be updated from a larger number of pts. Conclusions: Multiple potentially actionable therapeutic targets were identified by cfDNA sequencing of pts with mCRPC. This novel methodology facilitates the yield of large quantities of high fidelity DNA from minimal quantities of plasma, and appears promising to serially and non-invasively profile tumor DNA and inform on clonal evolution in a time and cost-efficient manner.