tbuckley/cabot-search huggingface dataset:
Final results of a phase 1 trial of sorafenib, pemetrexed, and cisplatin in patients with advanced solid tumors.
Authors: Abeer F Alharbi, Mark N. Kirstein, Naomi Fujioka
Journal: Journal of Clinical Oncology (2018)

e14582 Background: To investigate the tolerability, safety, and pharmacokinetics of sorafenib administered in combination with pemetrexed and cisplatin in advanced solid tumors patients. Methods: Patients with advanced solid tumors refractory to standard treatment were eligible. Patients received cisplatin 75mg/m2 IV and pemetrexed 500 mg/m2 IV every 3 weeks. Sorafenib was administered as 200 mg or 400 mg orally twice daily, and escalated using a standard 3+3 design. Sorafenib and n-oxide metabolite pharmacokinetics were assessed in four patients. Data regarding post-treatment response, toxicities, time to progression (TTP) and overall survival (OS) were collected. Results: Sixteen patients were enrolled; 10 males (62.5%) and 6 females (37.5%), median age was 61.5 (range 49-74) years. The median number of cycles was 4 (range 1-12). No grade 4 toxicities occurred within the 200 mg sorafenib dose cohort (n = 7). Dose-limiting toxicities (DLT) within the 200 mg sorafenib cohort were all grade 3 and included fatigue, weakness, somnolence, syncope, hyponatremia, and hypoalbuminemia. Grade 3 DLT events at dose level 400 mg (n = 9) included hyponatremia (1), hypophosphatemia (1), hypomagnesemia (1), hyperlipasemia (1), hyperglycemia (1), fatigue (1), dizziness (1), diarrhea (1), nausea (1), UTI (1), hypertension (1), and palmar-plantar erythrodysesthesia (2). Two patients developed grade 4 pulmonary embolism, and one patient developed grade 4 neutropenia and anemia. A complete response was observed in one patient with urothelial carcinoma, who received 12 cycles. Twelve patients achieved at least stable disease. Response data was not available for 3 patients. The median time to progression (TTP) and overall survival (OS) were 4.37 months and 8.63 months (95%CI: 5.93- 22.2 months), respectively. Sorafenib maximum concentrations were similar between dose cohorts, indicating high between-subject variability. Conclusions: Sorafenib 400 mg is safe when administered with cisplatin and pemetrexed in advanced solid tumors patients. This study lays the groundwork for future research on combining sorafenib with pemetrexed and cisplatin for patients with refractory advanced solid tumors. Clinical trial information: NCT00703638.
IMGN853 (mirvetuximab soravtansine), a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC): Single-agent activity in platinum-resistant epithelial ovarian cancer (EOC) patients (pts).
Authors: Kathleen N. Moore, Lainie P. Martin, Ursula A. Matulonis, Jason A. Konner, Shelly Marie Seward, Todd Michael Bauer, David M. O'Malley, Raymond P. Perez, Woondong Jeong, Yinghui Zhou, Maurice William Kirby, Satishkumar Mohanavelu, Rodrigo Ruiz-Soto, Michael J. Birrer
Journal: Journal of Clinical Oncology (2016)

5567 Background: IMGN853 (mirvetuximab soravtansine) is an ADC, comprising a FRα-binding antibody linked to the tubulin-disrupting maytansinoid, DM4. Here we report on the IMGN853 monotherapy expansion cohort of pts with platinum-resistant EOC as part of an ongoing phase I dose escalation trial (NCT01609556). Methods: Patients were administered IMGN853 intravenously once every 3 weeks at 6.0 mg/kg using adjusted ideal body weight. Responses were assessed according to RECIST 1.1 and adverse events (AEs) evaluated by CTCAE v4.0. Results: A total of 48 EOC, primary peritoneal, or fallopian tube cancer pts (n = 45, 1, and 2, respectively) have been treated at 6.0 mg/kg: 2 in dose escalation; 46 in the platinum-resistant expansion cohort. Pts were heavily pretreated (median of 4 previous systemic treatments), with 100% prior platinum and taxane exposure. To date, objective tumor responses were observed in 19 pts for an overall response rate (ORR; confirmed and unconfirmed partial response [PR] or complete response [CR]) of 40%. Based on FRα expression, responses were seen in pts in each subgroup: 33% (3/9) low (25-49% of cells with ≥ moderate expression), 33% (5/15) medium (50-74% of cells with ≥ moderate expression), and 48% (11/23) high ( ≥ 75% of cells with ≥ moderate expression) expressers. The most commonly reported AEs ( > 25 % of pts) were diarrhea, blurred vision, fatigue, nausea, vomiting, peripheral neuropathy, and increased AST (aspartate aminotransferase); the majority of which were grade 1 or 2. The most frequent grade 3-4 drug related AEs were fatigue and hypotension (2 patients each - 4.2%). Four pts discontinued for AEs. Thirteen pts remain on IMGN853. The median duration of follow-up is 4.2 months. Conclusions: IMGN853 demonstrates encouraging signs of clinical activity in heavily pretreated platinum-resistant EOC pts with a manageable safety profile. Further, the ORR (48%) seen in the high FRα expression subset suggests that FRα expression may be a predictive biomarker for IMGN853 suitable for patient selection. Clinical trial information: NCT01609556.
An ultra-deep next generation sequencing method for cfDNA detection in NSCLC patients.
Authors: Yu Yao, Longgang Wei, Yuan Yuan, Pan Yu, Xin Wu, Zhenyu Zhang, Nan Duan, Jiaqi Zhu, Xuehong Meng, Yang Yu, Kejun Nan, Zhi Jiang
Journal: Journal of Clinical Oncology (2016)

e23084 Background: Targeted therapies based on gene status have dramatically improved PFS and OS in NSCLC patients. However, about 1/3 of advanced NSCLC patients can’t get enough tissue specimen to do gene sequencing. Circulating tumor DNA (ctDNA) offered a potential alternative. Since ctDNA is usually rare, novel ultrasensitive multiplex technologies are needed for ctDNA sequencing. Methods: We have developed an ultra-deep NGS method for somatic mutation detection. To validate the accuracy of SNV/Indel and fusion detection, reference samples were used, which were constructed by mixing DNA extracted from wild type human cell line with plasmid containing known SNV/ Indel, in dilution ranging from 0.5% to 10%, or mixing with DNA from cell lines carrying known fusion, in dilution ranging from 0.05% to 10%. Abundance of mutations were confirmed by 3D digital PCR. A panel including 23 cancer related core genes was used in the test, with full exon tiling, introns where rearrangement usually happen were also included. Finally, 41 sets of matched tumor and blood sample from IIIB-IV stage NSCLC patients were detected, to evaluate the concordance of test results between tumor tissue and ctDNA using the method. Results: By using the reference sample, our pipeline detected all the SNV /Indel over 1% with 100% sensitivity and 100% specificity, for 0.5%-1% mutant, the sensitivity and specificity was 90% and 90% respectively. Moreover, the abundance of mutant detected by NGS was consistent with 3D digital PCR results(R2= 0.828). All the fusions over 0.1% were detected; fusions over 0.2% were stably detected through all the 5 replicates. Using this pipeline to detect 41 sets of NSCLC patient samples, 30/41 tumor tissues had at least one mutation, 21/30 were detected in the matched blood sample, with 100% specificity, and the total consistency was 78%. For EGFR gene, 20/41 tumor tissue detected mutations, 15/20 were detected in the matched blood sample, the concordance was 88%. Seven fusions were detected, 5/7 were consistent between plasma and tumor tissue. Conclusions: We developed a reliable ultra-deep NGS method to detect ctDNA. This novel technology has a great potential for noninvasive gene mutation detection.
Pan-cancer genomic variation characteristics of <i>CDKN2A/CDKN2B/CCND1</i> in Chinese patients.
Authors: Songfeng Yu, Qiyong Li, Lei Dai, Peng Zhao, Li Zhuang, Yigang Qian, Li Yang, Ming Wang, Yuandong Wang, Honglin Guo, Ruobing Ma, Ming Yao
Journal: Journal of Clinical Oncology (2018)

e13519 Background: Cell cycle regulation plays a vital role in cancer development, and targeting the aberrant pathway using CDK4/6 inhibitors shows reliable efficacy in tumor suppression. Characteristics of these genes and the co-existing genomic variations in pan-cancer study had not been fully evaluated. Methods: FFPE samples of 515 Chinese patients (pts) including 317 males and 198 females with a mean age of 58 years were collected for next generation sequencing based panel of 450 cancer genes. The cohort included 314 lung adenocarcinomas (ADC), 128 colorectal carcinomas (CRC) and 73 hepatocellular carcinomas (HCC). All classes of genomic alterations were assessed. Results: Genomic alterations of CDKN2A/CDKN2B/CCND1 were detected in 9.1% (47/515) of Chinese pts (with mutations in at least one gene). Variation frequencies of each gene in the whole cohort were 5.6%, 1.9% and 3.5%, respectively, more common in HCC (16.0%) and ADC (10.5%) than CRC (1.6%). Frequently co-occurring mutated genes of CDKN2A/CDKN2B/CCND1 were TP53 (72.3%), EGFR (46.8%), FGF19 (29.8%), TERT (25.5%), FGF3 (23.4%) and FGF4 (23.4%). CCND1-FGF3/4/19 11q13 amplificons were observed in 10 pts (7 ADCs and 3 HCCs). In TCGA, CDKN2A/CDKN2B/CCND1 were detected in only 2.2% patients of the pan-cancer cohort, which was relatively more common in ADC (4.8%) and rare in HCC (0.5%) and CRC (0.9%). Eight pts including 4 pancreatic cancers, 3 NSCLC and 1 prostate cancer had been treated with palbociclib for at least one month. According to RECIST, one pancreatic cancer pt had PR, and one NSCLC pt showed SD lasting 3 months. Conclusions: Our study revealed that mutation frequency of CDKN2A/CDKN2B/CCND1 was higher in Chinese pts than Western cohort. A very small scale retrospective analysis of palbociclib effectiveness demonstrated the limited antitumor activity of CDK inhibitors in pts so far. Integrating pan-cancer genomic profile study with clinical features might be useful in identifying the pts who might potentially benefit more from such treatment.
Patient preference for receiving information about long-term symptoms.
Authors: Antonia Vickery Bennett, Carolyn E. Eberle, Stephen Matthew Schleicher, Emeline Aviki, Sujata Patil, Ethan M. Basch, Jeff A. Sloan, Victoria Susana Blinder
Journal: Journal of Clinical Oncology (2017)

e21681 Background: Maintaining quality of life with minimal symptoms is an important goal of cancer treatment. We surveyed patients undergoing cancer treatment about their preferences for information about the long-term symptom burden associated with their current treatment. Methods: Patients undergoing active cancer treatment were enrolled at two large cancer centers from 1/2014 to 7/2015. At the time of enrollment patients reported their household income, employment, performance status and their agreement with the statement, “It would be useful to know the percentage of patients having persistent symptoms more than a year after getting the same treatment I am getting.” Treatment intention (curative vs. palliative) was reported by the treating oncologist. Results: 196 patients completed the survey. The mean age was 55.7 (range 20-80); 54% were female, 69% were white, and 60% were receiving palliative treatment. The majority (83%) of patients either strongly agreed or somewhat agreed that it would be helpful to have information about future symptoms. In univariable analyses, this preference did not significantly differ based on patient-reported performance status, sex, age, treatment intent, race, or household income. Using a more stringent criterion to dichotomize the outcome, 59% of participants strongly agreed that it would be helpful to have information about future symptoms. Patients undergoing treatment with curative intent were significantly more likely to strongly agree (72% vs. 51%, p = 0.0035). In a multivariable analysis adjusting for age, sex, income level, employment status, and patient-reported performance status, participants undergoing curative versus palliative treatment had 3.1 times the odds (95% CI 1.47-6.65) of strongly agreeing. Conclusions: The majority of patients undergoing cancer treatment wanted to know what symptoms to expect in the future, and this was independent of patient demographics. Patients undergoing treatment with curative intent are significantly more likely to want this information than patients undergoing palliative treatment. Symptom data collected through research studies and registries should be summarized by treatment and other key predictors and made available to patients.
Does chemotherapy, radiotherapy, or hormonal therapy increase the risk of multiple cancers? A pilot study at University of Florida, Jacksonville—2011-2016.
Authors: Karan Seegobin, Estela G. Staggs, Robina Khawaja, Satish Maharaj, Shiva Gautam, Carmen Smotherman, Fauzia N. Rana
Journal: Journal of Clinical Oncology (2018)

e13559 Background: We observe the occurrence of multiple cancers in patients diagnosed with one cancer. Individuals with cancer are at increased risk for subsequent tumours. This risk is multi-factorial. Use of chemotherapy and radiotherapy has improved survival. Unfortunately, it comes at a price due to therapy-related malignancies. In some reports occurrence of a second cancer is highest 5-10 years after diagnosis of the first. We aim to further understand the role chemotherapy, radiotherapy and hormonal therapy has in the development of another different primary cancer. Methods: Our cancer database was used to identify patients with the diagnosis of a first cancer in 2011. A total of 867 patients were obtained. The number of different primary cancers occurring prospectively from 2011 over a 5 year period were observed. Those without exposure to any of these therapies, as well as those who did not follow up at our institution were excluded leaving 602 patients. Results: 602 patients had either radiotherapy, chemotherapy, hormonal therapy or a combination of these. Of this 602, 24 patients had a second cancer within 5 years from the first diagnosis and there were no patients with a third cancer. The rates of second cancers are as follows: patients with chemotherapy alone (4.35%), radiotherapy alone (2.87%), hormonal therapy alone (4.55%), and those with any combination therapy (4.70%);[p=0.738]. Of the second cancers reported after 2011, renal (11.6%), hematological (11.6%), and lung cancer (9.3%) were the most frequent reported. Rates of second cancers in males vs females were 5% and 7% respectively [p=0.467]; also rates in whites vs non whites, were 5% and 6% respectively [p=0.318]. Conclusions: Second cancers can occur after treatment of one cancer. There was no significant difference in the rates of second cancers after exposure to chemotherapy, radiotherapy, hormonal therapy or combination of these at a 5 year mark. There should be heightened awareness among physicians in the detection of new cancers, especially within five years after diagnosis of the initial one.
Checkmate 816: A phase 3, randomized, open-label trial of nivolumab plus ipilimumab vs platinum-doublet chemotherapy as neoadjuvant treatment for early-stage NSCLC.
Authors: Patrick M. Forde, Jamie E. Chaft, Enriqueta Felip, Stephen Broderick, Nicolas Girard, Mark M. Awad, Keith Kerr, Anne Blackwood-Chirchir, Rong Yang, William J. Geese, Julie R. Brahmer
Journal: Journal of Clinical Oncology (2017)

TPS8577 Background: At initial diagnosis, 20% of patients (pts) with NSCLC present with early-stage disease. The 5-year overall survival (OS) rate after surgery for stage IB–IIIA NSCLC is 25%–60%. Addition of adjuvant chemotherapy to surgery only provides a 5% absolute OS benefit at 5 years. Neoadjuvant treatment with immune checkpoint inhibitors may extend OS in early-stage NSCLC by enhancing systemic immunity and eradicating micrometastatic disease. In contrast to the adjuvant setting, the neoadjuvant setting is associated with a higher tumor burden, the presence of abundant tumor antigens, and the consequent potential for tumor-associated neoantigen presentation to the immune system. In an ongoing feasibility trial in pts with stage IB–IIIA NSCLC, nivolumab (nivo; a fully human PD-1 immune checkpoint inhibitor antibody) given alone as neoadjuvant treatment induced a major pathological response (MPR; &lt; 10% residual viable tumor cells) rate of 39% (7/18), did not delay or interfere with surgery, and was not associated with new safety signals. In a phase 1 study in pts with stage IIIB/IV NSCLC, first-line nivo + ipilimumab (ipi; a CTLA-4 immune checkpoint inhibitor antibody) showed a greater radiologic objective response rate than nivo alone (39% vs 23%). These data provided the rationale for Checkmate 816 (NCT02998528), a phase 3 study evaluating nivo + ipi vs platinum-doublet chemotherapy as neoadjuvant treatment for early-stage NSCLC. Methods: Approximately 326 pts aged ≥18 years with resectable stage IB/II/IIIA NSCLC, ECOG performance status 0–1, pulmonary function capable of tolerating lung resection, and available lung tumor tissue will be enrolled in North America, South America, Europe, and Asia. Pts are ineligible if they have autoimmune disease or had received prior treatment with immune checkpoint inhibitors. Pts will be randomized to receive nivo + ipi or platinum-doublet chemotherapy. The primary endpoint is MPR rate. Secondary endpoints include event-free survival, OS, and complete pathological response. Start date is January 2017. The estimated primary completion date is July 2019. Clinical trial information: NCT02998528.
A machine learning approach to enable evidence based oncology practice: Ranking grade and applicability of RCTs to individual patients.
Authors: Naresh Ramarajan, Rajendra A. Badwe, Paul Perry, Gitika Srivastava, Nita S Nair, Sudeep Gupta
Journal: Journal of Clinical Oncology (2016)

e18165 Background: In-clinic application of Randomized Controlled Trial (RCT) results is complex. There is variability in conclusions of RCTs studying similar therapies and it is difficult to estimate their external validity. Individual patient data meta-analyses attempt to address these issues with aggregate and subgroup results, but are only possible many years later. We have developed Machine Learning (ML) based tools to predict whether results of any RCT will agree with that of subsequent meta-analyses, and provide real-time ranking of RCTs based on the predicted agreement. Methods: The Grade Index algorithm considers quality of an RCT based on methodology features such as sample size, endpoint, number of years of follow-up, etc. The Applicability Index algorithm considers similarity of an index patient to a trial population based on features such as age, tumor size, etc. The algorithms predict agreement on direction of effect (experimental arm better or equal to control) between any RCT and meta-analyses aggregate and subgroup results, respectively. Primary endpoint is percent accuracy of predicted agreement of an RCT with recently published EBCTCG (Early Breast Cancer Trialists Cooperative Group) meta-analyses. Results: A comprehensive sample of 210 published early breast cancer RCTs conducted between 1976 and 2015 (total sample size of 159,488 patients) was curated from MEDLINE. Nine features pertaining to the quality of an RCT and nine other features describing disease and patient information from the demographic data tables were selected. Over 100 state of the art ML algorithms such as Support Vector Machines (SVM) and Random Forest were systematically evaluated. The winning Grade Index algorithm and the Applicability Index algorithms achieved accuracies of 98% and 95%, respectively. Conclusions: Quality related features as well as demographic data of an RCT can be used by the Grade Index and Applicability Index algorithms, respectively, to rank agreement with subsequent meta-analyses. These ranks are used in a clinically validated informatics system to generate real time evidence based treatment recommendations for breast cancer patients.
Preliminary Phase II results of a multicenter, open-label study of nazartinib (EGF816) in adult patients with treatment-naïve <i>EGFR</i>-mutant non-small cell lung cancer (NSCLC).
Authors: Dong-Wan Kim, Daniel Shao-Weng Tan, Santiago Ponce Aix, Lecia V. Sequist, Egbert F. Smit, Toyoaki Hida, James Chih-Hsin Yang, Enriqueta Felip, Takashi Seto, Christian Grohé, Juergen Wolf, Jinnie Ko, Mariama Diallo, Philippe Pultar, Monica Giovannini, Sang-We Kim
Journal: Journal of Clinical Oncology (2018)

9094 Background: Nazartinib (EGF816) is a third-generation EGFR-TKI selective for activating and T790M mutations while sparing wild-type EGFR. In the Phase I part of a Phase I/II multicenter study of nazartinib in EGFR-mutant NSCLC (NCT02108964), the recommended Phase II dose was 150 mg QD. Preliminary safety and efficacy results are presented from the Phase II expansion in treatment-naïve patients (pts) with EGFR-mutant NSCLC. Methods: Pts (ECOG PS 0−1) received nazartinib 150 mg QD. Primary objective: evaluation of antitumor activity (overall response rate [ORR]) per blinded independent review committee (BIRC). Secondary objectives: characterization of safety/tolerability, and further efficacy endpoints (including time to response and progression-free survival [PFS]). Results: At the data cut-off 31 Aug 2017, 40 pts had been enrolled; median age 63.5 years, 70% Asian, 65% female, 52.5% ECOG PS 1, 16/40 (40%) pts had brain metastases at screening; 3/40 (7.5%) pts had discontinued (2 due to progressive disease and 1 due to AE) and 37/40 (92.5%) pts remained on treatment. Median duration of exposure was 16.1 wks. The most frequent (≥20%) any-grade (Gr) AEs were maculopapular rash (30%), diarrhea (28%), and stomatitis (23%). Gr 3 AEs occurred in 10/40 (25%) pts, most commonly (≥5%) maculopapular rash in 4/40 (10%) pts and hypokalemia in 2/40 (5%) pts; there were no Gr 4 AEs. Pts (n = 24) who were enrolled ≥15 weeks before the data cut-off date were considered evaluable. In these pts, the confirmed ORR by BIRC was 67% (1 CR/15 PRs); the unconfirmed ORR by BIRC was 75% (1 CR/17 PRs, including 2 pts with unconfirmed PRs still ongoing at the data cut off); disease control rate was 96%. Duration of response and PFS data were still immature at the data cut-off. Conclusions: Oral nazartinib demonstrated a tolerable safety profile; maculopapular rash, atypical of EGFR-TKIs, was managed with minimal dose adjustment. Promising efficacy in treatment-naïve pts with EGFR-mutant NSCLC was seen despite a high number of pts with brain metastases. At the data cut-off, 37/40 pts were still on treatment. Clinical trial information: NCT02108964.