tbuckley/cabot-search huggingface dataset:
Host metabolic factors and prognosis in patients treated with immune checkpoint inhibitors for advanced malignancies.
Authors: Federica Biello, Marco Audisio, Silvia Genestroni, Gloria Borra, Francesca D'Avanzo, Gaetano Lacidogna, Andrea Pietro Sponghini, David Rondonotti, Laura Forti, Francesca Vignani, Francesco Barone Adesi, Massimo Di Maio, Antonio Sica, Alessandra Gennari
Journal: Journal of Clinical Oncology (2019)

e14162 Background: It is well established that an altered host metabolism has an impact on cancer outcome, possibly mediated by several mechanisms, including hyperglicaemia, hyperinsulinemia and presence of chronic inflammation. The aim of our analysis was to evaluate the correlation between host metabolism and clinical outcome in patients with advanced melanoma, kidney and non-small cell lung cancer (NSCLC), treated with immune checkpoint inhibitors (anti-CTLA4, anti PD1 and anti PDL1). Methods: The relationship between presence of type 2 diabetes mellitus (DMII) at baseline and outcome was assessed in 187 patients treated with immune checkpoint inhibitors in two cancer centers. Progression Free Survival (PFS) and Overall Survival (OS) were calculated by Kaplan-Meier estimation; multivariate Cox analysis was performed according to age, gender, BMI (normal &lt; 25 kg/m2, overweight 25-30 kg/m2, obese &gt; 30 kg/m2), type of cancer and line of treatment. Results: One-hundred-sixty-eight patients were available for our analysis. Twenty-eight patients (17%) were diabetic at baseline. Median age was 65 (range 25-80); 83 patients were males (49%); 82 (48%) had advanced melanoma, 83 (49%) NSCLC and 3 (3%) kidney cancer. One-hundred-two (60%) patients had BMI &lt; 25, 51 (30%) were overweight and 16 (10%) were obese. The first line of treatment was immunotherapy in 83 (49%) patients. By univariable analysis median PFS was 4.2 months in non diabetics vs 6.4 in diabetics patients (HR 0.95; 95%CI 0.58-1.58); median OS was 6.17 and 9.1 months, respectively (HR 1.00; 95%CI 0.58-1.75). At multivariable analysis, taking into account DMII, BMI, sex, age, line of treatment and type of cancer, we found that BMI ≤25 was associated with a two fold increase in risk of progression (PD) or death (p = 0.005), whereas patients who received immunotherapy as second or subsequent line had a two fold increase in risk of PD or death (p = 0.003). Conclusions: The results of our analysis show that in patients with advanced cancer treated with immune checkpoint inhibitors, the presence of DMII does not adversely affect the clinical outcome. Conversely, lower BMI was associated with a significantly worse PFS and OS, independently from type of cancer, age and gender. As expected, patients who received immunotherapy in later lines of treatment had a significantly shorter survival.
Phase I safety and pharmacokinetic study of KN035, the first subcutaneously administered, novel fusion anti-PD-L1 antibody in Japanese patients with advanced solid tumors.
Authors: Toshio Shimizu, Takako Eguchi Nakajima, Ni Lu, Shilin Xue, Wenlian Xu, Meng Fu, Walt Cao, Haolan Lu, David Liu, RuiPing Dong, Xiaoxiao Wang, Pilin Wang, Danming Zhu, Ting Xu, John Gong
Journal: Journal of Clinical Oncology (2019)

2609 Background: KN035 is a novel fusion protein of humanized anti-PD-L1 single domain antibody and human IgG1 Fc, formulated for subcutaneous (SC) injection. A phase I safety and pharmacokinetic (PK) study was conducted in Japanese patients. Methods: Patients with advanced solid tumors were treated with KN035 SC once every-7-days (QW) or once every-14-days (Q2W) schedules with the dose limiting toxicities (DLT) evaluation period of 28 days. For the QW schedule, the starting dose was 1 mg/kg (n=3) with escalations to 2.5 (n=4), and 5 (n=3) mg/kg. For the Q2W schedule, 6 patients were planned at the dose levels of 2.5 and 5 mg/kg. Results: No DLT was observed up to the highest dose level of 5 mg/kg QW. No maximum tolerated dose (MTD) was reached. Among evaluable treated subjects (n=14), there were two confirmed partial responses. Preliminary PK analysis suggested that after SC administration, KN035 was slowly absorbed (Tmax ∼ 4 d) and the mean residual time (MRT) was 21 days. Apparent clearance (CL/F) and volume of distribution (Vz/F) were on average 0.58 L/day and 11 L, respectively. Plasma levels generally decreased mono-exponentially with an average terminal elimination half time around 13 days after reaching the peak concentration post SC administration. Exposures of KN035 increased approximately proportionally with dose. Trough concentrations were maintained above 15 µg/mL post administration of 5 mg/kg Q2W. No apparent exposure-body weight relationship was observed. Conclusions: KN035 exhibits a favorable safety profile in patients with advanced malignancies and preliminary results demonstrate encouraging anti-tumor activity. Based on PK data from the Q2W schedule, a fixed dose with less frequent dosing schedule of every 3 or 4 weeks is presently being evaluated. Clinical trial information: NCT03248843.
Comprehensive analysis of immune indicators provides prognostic markers for early stage non-small cell lung cancer.
Authors: Xiao Ding, Jiuwei Cui
Journal: Journal of Clinical Oncology (2019)

e14276 Background: Adjuvant chemotherapy has been established as a standard for patients with early stage NSCLC after complete tumor resection, but the 5-year survival rate can only increase by about 5%. Given its high morbidity and mortality, new biomarkers are needed to predict clinical response and prognosis of resected NSCLC. The expression of MHC-I, PD-L1 and CD8 + TILs were detected in this study to investigate the potential prognostic markers in patients with early stage NSCLC. Methods: Tissue of 125 patients with surgically resected NSCLC (stage I-III) were obtained from the First Hospital of Jilin Universtiy. MHC-I, PD-L1 and CD8 + TILs were detected with immunohistochemistry. The association between their expression levels and patients’ prognosis was analyzed. Results: MHC-I was down-expressed, and PD-L1 was up-expressed in NSCLC tissues compared with the para-cancer tissues. CD8 + TILs could be seen in tumor stroma and nest. PFS and OS was poorer in MHC-I low group compared with MHC-I high group (P &lt; 0.05). PFS and OS in PD-L1 − group tended to be longer than the PD-L1 + group, but the difference was not significant (P &gt; 0.05). For CD8 + TILs, PFS and OS of the CD8 inflamed group were longer than the CD8 non-inflamed group (P &lt; 0.05). With multivariate analysis, we found that MHC-I and CD8 + TILs might be independent prognostic factors of NSCLC (P &lt; 0.05). Based on the PD-L1 and CD8 + TILs expression, we divided the patients into four subgroups: PD-L1 + /CD8 inflamed , PD-L1 + /CD8 non-inflamed , PD-L1 − /CD8 inflamed , and PD-L1 − /CD8 non-inflamed . Statistical differences were achieved both in PFS and OS (P &lt; 0.05). PFS and OS of the PD-L1 + /CD8 inflamed and PD-L1 − /CD8 inflamed group were longer than the other two groups. Patients with PD-L1 + /CD8 non-inflamed experienced the worst PFS and OS. Besides, we divided the patients into four subgroups according to their MHC-I and CD8 + TILs expression conditions: MHC-I high /CD8 inflamed , MHC-I high /CD8 non-inflamed , MHC-I low /CD8 inflamed , and MHC-I low /CD8 non-inflamed . Statistical differences were achieved both in PFS and OS of these subgroups (P &lt; 0.05). PFS and OS of the MHC-I high /CD8 inflamed group were longer than the other three groups. Patients in MHC-I low /CD8 non-inflamed group experienced the worst PFS and OS. Conclusions: It was reported for the first time that the combination of PD-L1 and CD8 + TILs, MHC-I and CD8 + TILs suggested impressive prognostic values in early stage NSCLC in this study. The comprehensive analysis of immune indicators may provide prognostic markers for early stage NSCLC.
Preliminary safety results of a phase II study investigating pembrolizumab in combination with postoperative intensity modulated radiotherapy (IMRT) in resected high risk cutaneous squamous cell cancer of the head and neck.
Authors: Shlomo A. Koyfman, Brian Gastman, Allison T. Vidimos, Nikhil Purushottam Joshi, Jennifer Lucas, Christine Poblete-Lopez, Alok Vij, Jon Meine, Brian B. Burkey, Jamie Ku, Eric Lamarre, Brandon Prendes, Joseph Scharpf, Steven D Billings, Julia Samsa, Shelley Beth Robinson, David J. Adelstein, Jessica Lyn Geiger
Journal: Journal of Clinical Oncology (2019)

e21056 Background: High risk cutaneous squamous cell cancer of the head and neck (cSCC-HN) have suboptimal outcomes with surgery and postoperative radiation. We report preliminary safety outcomes of a phase II study (NCT03057613) exploring the safety and efficacy of the addition of Pembrolizumab to postoperative IMRT. Methods: Patients with cSCC-HN were eligible for this IRB approved study if they had resection of all gross disease and demonstrated (a) invasion of the skeleton or skull base; (b) node positive disease; (c) or a tumor &gt; 2cm with ≥1 of the following risk factors: recurrent disease, perineural invasion, lymphovascular space invasion, poorly differentiated, positive margins, satellitosis or in-transit metastases. Immune competent pts and those with CLL were eligible. This study aimed to accrue 34 evaluable patients to assess a primary safety endpoint of dose limiting toxicity (DLT) defined as any grade ≥3 toxicity at least possibly related to the immunotherapy. Assuming toxicity of &lt; 20% is acceptable and &gt; 40% is unacceptable, if ≥11 of 34 (32%) patients experienced a DLT, the regimen would be considered unsafe. Results: Of 15 pts already enrolled on this study, 11 have completed the protocol treatment. There were no DLTs observed to date. Grade 2 immune related toxicity was seen in two patients, one with bullous pemphigoid and another with lymphopenia and peripheral neuropathy and weakness in his hands in the setting of a prior cervical spine injury. Both responded to steroids and recovered completely. Based on this initial cohort, the 95% confidence intervals (CI) on DLTs for the entire cohort is 0-28%. Using the most conservative CI of 28%, the likelihood of 11 of the remaining 23 patients experiencing a DLT is 3.4%. Assuming a CI of 20%, the risk is 0.3%. None of the 11 pts who have completed protocol therapy have experienced a recurrence. Conclusions: The addition of Pembrolizumab to postoperative IMRT in high risk cSCC-HN is safe and will be studied in a randomized phase III adjuvant study (Keynote 630). This phase II study will continue to enroll CLL patients to assess safety and efficacy signals in this unique higher risk population. Clinical trial information: NCT03057613.
Open label, phase II trial of neoadjuvant TAK-228 plus tamoxifen in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor type 2 (HER2)-negative breast cancer-ANETT.
Authors: Emre Koca, Polly Ann Niravath, Joe Ensor, Tejal Amar Patel, Xiaoxian Li, Pej Hemati, Helen Wong, Wei Qian, Toniva Boone, Jing Zhao, Priya V. Ramshesh, Adam Louis Cohen, Asha Murthy, Sindhu Nair, Jorge German Darcourt, Anna Belcheva, Virginia G. Kaklamani, Jenny Chee Ning Chang
Journal: Journal of Clinical Oncology (2019)

584 Background: Neoadjuvant endocrine therapy is standard care for women with hormone receptor-positive breast cancer. However, both primary and acquired endocrine resistance is not uncommon, thereby limiting efficacy. [1] The PI3K-Akt-mTOR pathway is a major mediator of endocrine resistance. [2,3] Therefore, we determined the efficacy and safety of the mTORC1/2 inhibitor TAK-228 in combination with tamoxifen in neoadjuvant setting. Methods: In this single-arm, open-label phase II trial, newly diagnosed patients with stage I−III ER-positive, HER2-negative breast cancer received TAK-228 (30 mg weekly) and tamoxifen (20 mg daily) for 16 weeks until 2-4 weeks prior to surgery. The primary endpoint was the change in Ki67 after 6 weeks. Secondary endpoints included pathological complete response rate (pCR), preoperative endocrine prognostic index (PEPI) score, and safety. Results: Of the 28 patients enrolled in the study, 3 were excluded due to non-compliance. Mean patient age was 51.7 years. Most patients had stage I or II disease (12 [43%] each); 4 (14%) had stage III disease. Mean Ki67 was significantly lowered from baseline to Week 6 (17.2% vs. 15.2%, p = 0.0023). Interestingly, mean Ki67 increased to 20.1% from baseline to the time of surgery. This may have been due to a rebound effect, as TAK-228 was discontinued 2-4 weeks prior to surgery. Tumor size also significantly decreased from baseline to surgery, with a median decrease of 0.75 centimeters (p &lt; 0.0001). PEPI score was intermediate risk (score 1−3) in 6 patients and high risk group (score ≥4) in 15 patients. No patients achieved a PEPI score of 0 and no pCR was achieved. Overall, the combination was well tolerated, the most common side effects were nausea (72%), vomiting (72%), fatigue (72%), mucositis (45%), and headache (45%). The any Grade 3 AE rate was 7.7%. Conclusions: The TAK-228 and tamoxifen combination was found to be an effective neoadjuvant strategy with a favorable safety profile in newly diagnosed patients with hormone receptor-positive breast cancer. Further molecular analysis (PI3K-Akt-mTOR pathway) are pending and will be presented. Clinical trial information: NCT02988986.
Participant hopes and expectations regarding outcomes of genomic sequencing research in pediatric oncology.
Authors: Jonathan M Marron, Emily Quach, Yana Pikman, Katherine A. Janeway, Jennifer W. Mack
Journal: Journal of Clinical Oncology (2019)

10020 Background: Tumor genomic sequencing is rapidly becoming more integrated into pediatric oncology, but for only a minority of individuals does sequencing identify new treatment options or impart an increased chance of cure. Retrospective data show that participants have high hopes for this promising technology, but patient/parent hopes and expectations for the outcomes of genomic sequencing have not previously been evaluated prospectively. Methods: Surveys were administered prospectively to eligible enrollees (young adult patients ≥18y with relapsed/recurrent cancer, rare cancers, and those with poor prognoses, or parents of patients &lt; 18y) prior to return of sequencing results in two clinical sequencing studies through the GAIN (NCT02520713) and LEAP (NCT02670525) Consortia, across 18 pediatric cancer centers. Using previously validated measures, participants were queried about what they most hoped for and thought most likely to happen (most expected) as a result of participating in the sequencing study. Comparisons were made between hopes and expectations using McNemar’s test. Separate multivariate models assessed predictors of most hoping for, and most expecting, increased chance of cure as a result of participating. Models were adjusted for gender, race, disease (leukemia/solid tumor), highest education level achieved, and survey participant (patient/parent). We present interim survey results for 124 participants (67% response rate) who completed surveys between 10/15/17 (GAIN) or 9/1/16 (LEAP) and 1/15/19. Results: 58% (70/121) of respondents selected increased chance of cure as their greatest hope in participating; only 21% (25/119) reported cure as their greatest expectation (p &lt; 0.005). 28% (34/121) most hoped their participation would help cure future patients, and 45% (54/119) most expected this result (p &lt; 0.005). Only 8% (10/121) most hoped to learn more about their/their child’s cancer, but 21% (25/119) most expected this result (p = 0.006). In multivariate analyses, education beyond college level was associated with most hoping for cure as a result of sequencing (OR 2.7 95% CI [1.2, 5.8], p = 0.016). A solid tumor diagnosis was associated with most expecting cure in this setting (OR 2.7 [1.0, 7.2], p = 0.048). Conclusions: Participants derive great hope from participating in pediatric cancer genomic sequencing research, but expectations are more tempered. Some subgroups express heightened expectations of cure, however, potentially identifying target populations for educational intervention.
Evolve: A post PARP inhibitor clinical translational phase II trial of cediranib-olaparib in ovarian cancer—A Princess Margaret Consortium – GCIG Phase II Trial.
Authors: Stephanie Lheureux, Ana Oaknin, Swati Garg, Jeffrey Bruce, Neesha C. Dhani, Ainhoa Madariaga, Luisa Bonilla, Yeh Chen Lee, Ilaria Colombo, Gita Bhat, Valerie Bowering, Justin White, Sarah Accardi, Susie Tan, Marsela Braunstein, Katherine Karakasis, Zhihui (Amy) Liu, Trevor John Pugh, Amit M. Oza
Journal: Journal of Clinical Oncology (2019)

5521 Background: PARP inhibitors (PARPi) are approved therapies in high grade serous ovarian cancer (HGSOC). There are few studies after PARPi progression and correlation with dynamic changes in resistance. We hypothesized that PARPi resistance could be overcome by adding an anti-angiogenic. Methods: We report the first phase 2 trial assessing the combination of olaparib and cediranib after PARPi failure in HGSOC. This investigator initiated study included three cohorts of 10 evaluable patients (pts): i) platinum sensitive post PARPi (PS), ii) platinum resistant post PARPi (PR) and iii) exploratory cohort of pts re-challenged with chemotherapy post PARPi progression (PE) (NCT02681237). The primary objective was to determine objective response rate by RECIST v1.1 and progression free survival (PFS) at 16 weeks. Secondary objectives were to evaluate safety, PFS, overall survival (OS) and mechanisms of PARPi resistance. Pts who had radiographic progression on any PARPi were eligible. Archival tumor at initial diagnosis and baseline tumor biopsy at PARPi progression were mandatory. Pts received olaparib tablets 150mg BID with cediranib 20mg QD until progression or unacceptable toxicity. CT scans were performed every 8 weeks. Whole exome and RNA sequencing were performed on paired tumors tissues. Results: Thirty-four pts were enrolled. BRCA1/2 mutations were found in 9/11 PS, 8/10 PR and 7/13 PE pts. By RECIST1.1, four partial responses were observed (2 in PR and 2 in PE cohorts) and 18 stable disease. The 16−week PFS was 54.5% (31.8−93.6) in PS, 50% (26.9−92.9) in PR and 36% (15.6−82.8) in PE, respectively. OS at 1 year was 81.8% (61.9−100) in PS, 64.8% (39.3−100) in PR and 39.1% (14.7−100) in PE. Main related adverse events were anemia, hypertension, diarrhea and fatigue, grade 3 &lt; 10%. Molecular analyses identified different mechanisms of PARPi resistance in ~77% of evaluable pts with matched pre-post PARPi progression biopsies such as reversion mutations in BRCA1/2 and other homologous repair (HR) genes; BRCA, HR and MDR upregulation, CCNE amplification and RIG-I like receptor downregulation. Conclusions: Treatment with olaparib-cediranib after PARPi failure was feasible and met the predefined bar for efficacy in each cohort. This is the largest clinical trial prospectively evaluating PARPi failure and correlating tissue genomic mechanisms of resistance. Clinical trial information: NCT02681237.
Oxaliplatin and 5-fluorouracil (FOLFOX) in advanced well-differentiated digestive neuroendocrine tumors: A multicenter national retrospective study from the French Group of Endocrine Tumors (GTE).
Authors: Paul Girot, Eric Baudin, Helene Senellart, Nadia Bouarioua, Olivia Hentic, Rosine Guimbaud, Thomas Walter, Aurelie Ferru, Guillaume Roquin, Guillaume Cadiot, Marc Pracht, Jean-Baptiste Girot, David Malka, Michel Ducreux, Julien Hadoux, Tamara Matysiak-Budnik, Yann Touchefeu
Journal: Journal of Clinical Oncology (2019)

4104 Background: Oxaliplatin-based regimens have shown promising antitumor activity in digestive neuroendocrine tumors (NETs), however the available data are limited. Our aim was to assess the tumor response and survival in a large series of patients treated with oxaliplatin and 5-fluorouracil (FOLFOX) for advanced digestive NETs.Oxaliplatin-based regimens have shown promising antitumor activity in digestive neuroendocrine tumors (NETs), however the available data are limited. Our aim was to assess the tumor response and survival in a large series of patients treated with oxaliplatin and 5-fluorouracil (FOLFOX) for advanced digestive NETs. Methods: All patients with advanced well-differentiated digestive NETs treated with at least 3 cycles of FOLFOX between 2004 and 2018 in 12 centers of the French GTE, were retrospectively included. Best response according to the RECIST 1.1 criteria, progression-free survival (PFS) and overall survival (OS) were evaluated. The prognostic factors for PFS were investigated by multivariate analysis using a Cox proportional hazard model including variables with a p value ⩽ 0.20 in univariate analysis. Results: One hundred and forty-nine patients were included. Primary tumor location was pancreas (n = 88), small intestine (n = 37), stomach (n = 7), rectum (n = 4) and unknown without lung tumor at CT scan (n = 13). Partial response rate was of 31% for pancreatic NETs, 13% for small intestine NETs, 14% for gastric NETs, 25% for rectal NETs and 38% for unknown primary NETs. Median PFS were, respectively, 9, 9, 14, 4 and 6 months, and median OS were 30, 28, 31, 25 and 15 months. Significant poor prognostic factors for PFS after FOLFOX in digestive NETs were: progressive disease (HR = 2.5, p = 0.018), hepatic involvement &gt; 50% (HR = 1.8, p = 0.009), prior targeted therapy (HR = 1.5, p = 0.048) and rectal primary tumor (HR = 4.2, p = 0.01). Among pancreatic NETs, the 9 insulinomas had a 22 months PFS versus 9 months for the others (p = 0.025), and serum glucose normalization was obtained in 8 out of 9 cases. Conclusions: FOLFOX has a promising clinical activity for gastroenteropancreatic NETs, especially in insulinomas.
Evaluating the American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) value frameworks for Food and Drug Administration (FDA) approved checkpoint inhibitors (CIs).
Authors: Sophie Feng, Yanshuo Cao, Eitan Amir, Eric Xueyu Chen
Journal: Journal of Clinical Oncology (2019)

6624 Background: Although the development of CIs has led to a dramatic change in the oncology landscape, these agents are associated with significant costs and toxicity. ASCO and ESMO have developed separate frameworks to define the value of emerging cancer treatments in order to encourage cost-effective therapies. We apply these frameworks to trials supporting FDA approvals of CIs and explore the correlation between these two scoring systems. Methods: We searched the FDA database for CIs and indications approved between January 1, 2011 and January 1, 2019. Only randomized phase II/III trials for solid tumors were included. Data on survival, toxicity and quality of life were extracted from the most recent publications by two reviewers independently. A trial showing a substantial benefit was defined as an ASCO score of ≥ 45, or ESMO Grade 4-5 (palliative setting) or Grade A/B (curative setting). Concordance for substantial benefit was assessed using Cohen’s Kappa while Spearman coefficients were used to determine the degree of correlation in individual scores. Results: We identified 40 FDA indications for 7 CIs. Of these, 18 indications based on Phase I/II single-arm trials were excluded. The remaining 22 indications were based on 21 randomized phase II/III trials (3 adjuvant, 18 metastatic). In the palliative setting, 73% and 86% trials showed substantial benefit based on ASCO and ESMO frameworks respectively [median ASCO score: 54.8, interquartile range (IQR) 46.2-64.0; median ESMO score: 5, IQR: 4-5]. 27% of trials were scored intermediate or low benefit by ASCO, while 9% were ineligible for ESMO scoring. Weighted kappa was 0.719 between the two frameworks. Spearman rho was 0.84. All 3 adjuvant trials were assigned ESMO grade A but low benefit with ASCO (median 37.7, IQR 20.5-40.9). Conclusions: In the palliative setting, the majority of trials supporting FDA approved CI indications demonstrated substantial benefit using both ASCO and ESMO frameworks. There was a strong correlation between the two frameworks. However, in the curative setting scores were discordant. The ASCO framework may require further refinement for adjuvant trials.