tbuckley/cabot-search huggingface dataset:
Disparity in PD-L1 expression between metastatic uveal and cutaneous melanoma.
Authors: Asad Javed, David Arguello, Curtis Johnston, Zoran Gatalica, Marlana M. Orloff, Michael J. Mastrangelo, Takami Sato
Journal: Journal of Clinical Oncology (2016)

9541 Background: Programmed death-ligand 1 (PD-L1) is expressed by various cells such as dendritic cells and tumor cells. In cancer, tumors evade the immune system by the interaction of PD-L1 with PD-1 receptor on activated T lymphocytes. This interaction forms the basis for the use of PD-1 inhibitors in cancer immunotherapy. The purpose of this study is to investigate differences in expression of PD-L1 on tumor cells and PD-1 receptor on tumor infiltrating lymphocytes (TILs) between metastatic uveal melanoma (MUM) and metastatic cutaneous melanoma (MCM). Methods: Biopsy specimens of MUM and MCM patients were analyzed for PD-L1 and PD-1 expression at a CLIA-certified lab (Caris Life Sciences). PD-L1 expression on melanoma cells was confirmed using validated, immunohistochemical cell-surface staining with an anti-PD-L1 antibody (SP142, positivity ≥ 5% tumor cells). PD-1 expression on TILs was confirmed using the anti-PD-1 antibody (MRQ-22, positivity ≥ 1 TILs per high-power field). In total, 106 MCM and 18 MUM specimens were analyzed for PD-L1 expression, while 89 MCM and 17 MUM specimens were tested for PD-1 expression. Results: Overall, 22/106 (20.8%) MCM specimens expressed PD-L1 (Table). The highest rate of expression was seen in lung metastasis. Interestingly, all 6 of the metastatic liver lesions showed no PD-L1 expression. In comparison, none of the uveal melanoma specimens showed PD-L1 expression. PD-1 expression was seen in 68/89 (76.4%) and 9/17 (53%) of MCM and MUM specimens, respectively. Conclusions: While PD-1 expression was seen in both MUM and MCM, there was a stark difference in PD-L1 expression between them (20.8% vs. 0%; p = 0.04). A complete absence of PD-L1 expression by MUM tumor cells might explain the lack of therapeutic response to PD-1/PD-L1 inhibition and suggests an alternative mechanism via which it evades the immune system. Cutaneous Melanoma Uveal Melanoma Site of metastasis Number of patients PD-L1 positive Site of metastasis Number of patients PD-L1 positive Lymph node 33 6/33 (18.2%) Liver 14 0% Lung 17 5/17 (29.4%) Other** 4 0% CNS 14 2/14 (14.3%) 18 0/18 Liver 6 0% Other* 36 9/36 (25%) 106 22/106 (20.8%) *Bone (n = 2), spleen (n = 2), skin, subcutaneous and soft tissue **Bone, mediastinum, lymph node and omentum
Treatment pattern of systemic therapies in patients with metastatic melanoma and BRAF mutation test.
Authors: Alex Z Fu, Zhiyi Li, Jackson Tang, Kris Grzegorzewski, Syed Mahmood, Tyler Whisman, Syed Quadri, Ying Qiu
Journal: Journal of Clinical Oncology (2016)

e21003 Background: The National Comprehensive Cancer Network (NCCN) recommends systemic therapy, including target therapy, immunotherapy, and chemotherapy, for metastatic melanoma (MM). BRAF mutations help inform the choice of therapy. This study aims to to describe the treatment pattern of mm patients before and after BRAF testing in the US. Methods: Two retrospective cohort studies were conducted using MarketScan commercial and Medicare supplemental databases and IMS PharMetrics Plus databases. Patients included those aged ≥ 18 years who had ≥ 1 mm diagnosis and received BRAF testing after mm diagnosis from August 1, 2011 to September 30, 2015. Patients with non-melanoma primary malignancy were excluded. Patients who received BRAF testing were identified based on Current Procedural Terminology (CPT) codes. Systemic therapies before and after BRAF testing were compared. Cost of the test and time from test to systemic therapy were evaluated. Results: 1,577 and 919 mm patients who received BRAF testing were included from MarketScan and Pharmetrics, respectively. Results from MarketScan analysis were as follows: the most recent systemic therapies before test were: no systemic therapy 96.3%; target therapy 0.3%; immunotherapy 2.5%; chemotherapy 1.0%, while the most recent systemic therapies after test were 58.4%, 12.1%, 23.0% and 6.5%, respectively. Median time from diagnosis to test and from test to the therapy was 34 and 47 days, respectively. The mean (±SD) costs of test was $515 (±$1011). Results from PharMetrics were similar. Conclusions: After BRAF testing, mm patients were more likely to receive systemic therapy. Many mm patients remained untreated after BRAF testing. MarketScan (N = 1577) Pharmetrics (N = 919) Age [mean, std] 57 13 57 12 Male 967 61% 577 63% Median days from mm diagnosis to test 34 36 Median days from test to systemic therapy 47 48 BRAF test cost [mean, std] $515 $1,011 $637 $1,227 Systemic therapy BEFORE test Target therapy 5 0.3% 5 0.5% Immunotherapy 39 2.5% 15 1.6% Chemotherapy 15 1.0% 64 7.0% No systemic therapy 1518 96.3% 835 90.9% First systemic therapy AFTER test Target therapy 191 12.1% 113 12.3% Immunotherapy 362 23.0% 179 19.5% Chemotherapy 103 6.5% 85 9.2% No systemic therapy 921 58.4% 542 59.0%
Discovery of COM701, a therapeutic antibody targeting the novel immune checkpoint PVRIG, for the treatment of cancer.
Authors: Spencer Liang, Ofer Levy, Sudipto Ganguly, Maya Kotturi, Ilan Vaknin, Liat Dassa, Meir Azulay, Zoya Alteber, Kyle Hansen, Chris Chan, Ling Leung, Sandeep Kumar, Doron Levin, Einav Safyon, Tal Friedman, Shirley Greenwald, Ran Salomon, Drew M. Pardoll, Mark White, Eran Ophir
Journal: Journal of Clinical Oncology (2017)

3074 Background: While inhibitors of CTLA4 and PD1 have emerged as effective cancer therapies, the majority of treated patients do not derive long term benefit. Employing our computational discovery platform, we discovered PVRIG as an immune suppressive molecule expressed on T and NK cells and identified COM701, an antibody (Ab) targeting human PVRIG that enhances T cell function and anti-tumor responses. Methods: Anti-human PVRIG Ab COM701 was identified as an antagonistic Ab that enhanced T cell function in multiple assays. Antagonistic anti-mouse PVRIG Abs and PVRIG deficient (PVRIG -/- ) mice were generated and characterized using syngeneic tumor models. Results: PVRIG was induced upon T cell activation, with long term activation leading to the highest expression. PVRL2 was identified as the ligand for PVRIG, placing PVRIG in the DNAM/TIGIT immunoreceptor axis. Compared to normal adjacent tissues, PVRIG and PVRL2 were both induced in the tumor microenvironment of several human cancers. To target PVRIG for therapeutic intervention, we identified COM701, a high affinity Ab that disrupts the interaction of PVRIG with PVRL2. COM701 enhanced CD8 T cell proliferation and IFN-g production in vitro and had an additive or synergistic effect on T cell activation when further combined with an anti-PD1 or anti-TIGIT Ab. Consistent with a checkpoint function for human PVRIG, mouse PVRIG -/- T cells showed increased function compared to wild type T cells. A surrogate antagonistic anti-mPVRIG Ab reduced growth of CT26 and B16 tumors when combined with an anti-PDL1 Ab in vivo. MC38 tumors also grew slower in PVRIG -/- mice compared to wild type mice and ex vivo analysis pointed to functional differences in anti-cancer immunity. Conclusions: We demonstrated that targeting PVRIG with COM701, a high affinity antagonistic Ab, increased human T cell function. We further showed that PVRIG was induced in the tumor microenvironment and that disruption of PVRIG/PVRL2 interaction resulted in reduced tumor growth in preclinical models. These data demonstrate that PVRIG is a promising target for the treatment of cancer and provide the rationale for COM701 as a potential cancer immunotherapy.
Final results of RENO study: Randomized phase II of oral vinorelbine or etoposide with cisplatin and chemo-radiation in stage III NSCLC. SLCG 10/02.
Authors: Mariano Provencio-Pulla, Ramon De Las Penas, Natividad Martinez Banaclocha, Raquel Marse Fabregat, Amelia Insa, Teresa Moran, Maria Angeles Sala Gonzalez, Bartomeu Massuti, Pilar Mut Sanchis, Ana Laura Ortega Granados, Jose Miguel Jurado, Jose Gómez-Codina, Angel Artal-Cortes, Maria Francisca Vazquez, Vanesa Gutierrez Calderon, Pilar Diz, Nuria Vinolas, Inmaculada Maestu, Carlos Camps, Dolores Isla
Journal: Journal of Clinical Oncology (2018)

e20521 Background: This study aims to compare efficacy and safety of two widely used combinations of cisplatin (P) in this setting: as etoposide (E) and vinorelbine. This last, in its oral formulation (oV) which has achieved comparable results as the IV formulation and patients (pts) prefer it. Methods: Pts between 18-75years, with histologically proven untreated and unresectable locally-advanced NSCLC (LA-NSCLC), adequate respiratory function, V20≤35% and ECOG-PS 0-1, were randomized 1:1 to oV-P arm: 2 induction cycles (cy) of oV-P followed by 2 cy more with RT; or to E-P arm: 2 cy of E-P concomitants to RT. Both arms with a total radiation dose of 66Gy administered 2 Gys daily. Primary endpoint was progression free survival (PFS) by RECIST 1.1. Secondary endpoints: overall response rate (ORR), overall survival (OS) and safety. With α-error of 0.05 (one-tailed test) and 0.1 β-error, median PFS unacceptable for the oV-P arm of 10 months (m) (p0) and a very acceptable of 15 m (p1), 122 eligible pts were required. Results: 140 pts from 23 institutions of SLCG were randomized between 08/2011-12/2014. 134 pts were treated (66 in oV-P and 68 in E-P arms). Results based on this 134 pts are presented. Median age 62 years [39-76]; PS 0/1, 45%/55%; current smoker 51%; squamous cell 51%; stage IIIB 54%. 244 and 131 cy were given in the oV-P and E-P arms, respectively. All irradiated pts in oV-P arm received at least 60Gy, 7 pts in the E-P arm received less than 60Gy (4 due to toxicity). 1 pt (1.5%) in oV-P arm and 12 pts (17.6%) in E-P arm presented esophagitis G3/4 (p = 0.002). ORR were 39 (61.9%) and 41 pts (65.1%) in the oV-P and E-P arms, respectively (p = 0.711). After 26.3 m [0.03-61] of follow-up, 77.9% pts progressed and 58.6% pts died. Median PFS was 10.8 m (CI95%; 7.5-14) in oV-P arm and 9.1 m (CI95%; 5.5-12.7) in E-P arm (p = 0.389). Median OS was 38 m (CI95%; 21.3-58.8) in oV-P and 27.1 m (CI95%; 19.3-34.9) in E-P arm (p = 0.547). Conclusions: Clearly both regimens achieve similar efficacy however oV-P has less toxicity, especially esophagitis G3/4. Clinical trial information: 2010-022927-31.
Reporting of research biopsies in clinical trials in oncology: Analysis of clinicaltrials.gov.
Authors: Christine Megerdichian Parseghian, Alda Tam, James C. Yao, Lee M. Ellis, Kanwal Pratap Singh Raghav, Michael J. Overman
Journal: Journal of Clinical Oncology (2018)

e18720 Background: Research biopsies are frequentlyincorporated within clinical trials in oncology, and are often a mandatory requirement for trial enrollment. However, limited information is available regarding the extent and completeness of research biopsy reporting. Methods: We searched www.ClinicalTrials.gov for all oncologic therapeutic clinical trials with completion dates between 01/01/03-01/01/13 with endpoint category terms including “biopsy” or “tissue”. Trials conducting only diagnostic biopsies (breast, thyroid, or bone marrow biopsies) and liquid biopsies were excluded. Credit was given for biopsy reporting for any mention of tissue biopsies in publications. Clinical trials were compared with the highest level of corresponding publication as a manuscript or registry report. The two-sided Fisher’s Exact Test was used for analysis. Results: A total of 123 clinical trials were identified, with a median of 46 patients (pts) enrolled per trial. After a median follow-up time of 5.8 years from trial completion, 101/123 trials (82%) reported trial results: published manuscripts in 82 and ClinicalTrials.gov reporting in 19. Reporting of trial results correlated with a higher study enrollment ( > 50 pts), P= 0.01, and later stage trials (Phase II/III), P= 0.002. Results from research biopsies were reported in 57/123 trials (46%). Rates varied by publication type: 52/82 manuscripts (63%) vs. 5/19 ClinicalTrials.gov reports (26%), P= 0.003. Academic sponsorship was associated with improved biopsy reporting (57% vs. 32%, P= 0.003). The proportion of reported research biopsies was higher in trials with mandatory biopsies (55% vs. 38%), and phase II/III trials (54% vs. 39%). Conducting paired biopsies, higher study enrollment, and multicenter trials did not correlate with improved reporting. Conclusions: Despite ethical obligations to report research biopsies, less than half of all trials that included a research biopsy-related endpoint on an international registry in actuality reported on these biopsy-related results. Improved efforts are needed by sponsors and investigators to report results obtained from research biopsies.
Retrospective analysis of taxane-based therapy in advanced small bowel adenocarcinoma (SBA).
Authors: Jeffrey D. Aldrich, Kanwal Pratap Singh Raghav, Gauri R. Varadhachary, Robert A. Wolff, Michael J. Overman
Journal: Journal of Clinical Oncology (2018)

e16263 Background: Recent genomic data has demonstrated SBA to be a molecularly unique entity when compared to colon or gastric cancer. A recent prospective study of single-agent nab-paclitaxel demonstrated a response rate of 20% (Overman et al. Annals of Oncology 2017). Based on these findings we sought to further explore the role of taxane-based therapy in this rare cancer. Methods: A single-center retrospective review of advanced SBA treated with taxane-based therapy from 2010 to 2017 at The University of Texas MD Anderson Cancer Center. All patients had pathology reviewed, received > 1 cycle of therapy, and had documented tumor response evaluation. Ampullary adenocarcinomas and patients enrolled on a clinical trial were excluded. Response assessment was based upon clinical notes and categorized as response, stable disease or progression. Kaplan Meier Analysis was utilized to calculate time to progression (TTP) and overall survival (OS). Results: 20 patients were treated with taxane-based therapy as single agent in 3 and combination therapy in 17 (gemcitabine combinations in 12; fluoropyrimidine combinations in 4, and platinum combination in 1). Patient characteristics were median age 54 years; 40% female; 80% Caucasian; small bowel site of 50% duodenum, 35% jejunum, 10% ileum, 5% jejunum/ileum; presenting stage of IV in 75%; primary tumor resection in 70%; median lines of prior therapy of 2 (range 0-3); KRAS mutation in 50%; predisposing conditions in 25% (3 inflammatory bowel disease and 2 Lynch syndrome). Best response was response in 30%, stable disease in 35%, and progressive disease in 35%. Response was seen in one patient treated with single agent therapy. Median TTP was 3.8 months (95% CI 2.9-4.6) and median OS was 10.7 months (95% CI: 3.1-18.3). Conclusions: This retrospective study demonstrates that taxane-based therapy has activity in advanced SBA. These findings support further investigation of taxane-based therapy in SBA.
Small cell transformation as a mechanism of resistance to immunotherapy of non-small cell lung cancer.
Authors: Jair Bar, Damien Urban, Teodor Kuznetsov, Moran Gadot, Oranit Zadok, Iris Kamer, Marina Perelman, Amir Onn, Efrat Ofek
Journal: Journal of Clinical Oncology (2018)

e21230 Background: Resistance to immune checkpoint inhibitors (ICPi) is common, either primary, or as acquired resistance after an initial response. Mechanisms of resistance are poorly documented. Methods: N = 375 ICPi treated NSCLC patients were identified in our working database (2016-2017). Cases with acquired resistance or a mixed response to ICPi who underwent a biopsy from a lesion progressing on ICPi treatment were analyzed. Results: 8 cases matched our criteria (Table). In two cases SCLC was identified in growing lesions’ biopsies. Both of them had a poor response to chemotherapy administered based on biopsy result. Conclusions: We have identified transformation to SCLC as a novel mechanism of resistance to ICPi. One of the tumors had baseline neuroendocrine features, suggestive of selection of resistant clones with neuroendocrine features as a mechanism of resistance. Selection of variant clones may lead to loss of immune-reactive epitopes and immunotherapy escape. Consideration should be given to re-biopsy of ICPi secondary resistance lesions. Pt Age sex Smoking First Biopsy Initial response to ICPi Time on ICPi till 2nd biopsy (mo) Site of PD biopsied 2nd biopsy IHC 1 69 M Yes Squ PR 11 Lung Squ NA 2 70 F Yes Squ Pseudo PD 16 Adrenal SCLC negative for squamous/basaloid markers,CD56+, TTF1+ 3 75 M Past ( > 10 y) Squ PR 6 Lung SCLC CD56+ , synaptophysin+, focally chromogranin+ , TTF1+.KI67 80% 4 68 M Past (1-10 y) Adeno Mixed 7 Lung Cores of loose fibrotic tissue with prominent chronic inflammatory infiltrate. No tumor identified NA 5 43 F Never Adeno PR 18 Rib Fat necrosis NA 6 61 M Yes Adeno PR 8 Lung Necrotizing undifferentiated tumor composed sheets of medium to large sized cells with pleomorphic hyperchromatic nuclei, morphologically compatible with carcinoma TTF1-, CK5/6-, and MNF116- 7 63 M Past (1-10 y) Adeno PR 9 Adrenal Adeno of lung CK7+, TTF1+, napsin+, CK20-, p40-, GATA3- and CK5/6- 8 74 F Yes Adeno PR 20 Breast Adeno with pleomorphic tumor cells TTF1+, Napsin A+ focal weak . GCDFP15- F: women. M: men. Squ: squamous cell carcinoma. Adeno: adenocarcinoma. SCLC: small cell lung cancer. IHC: immunohistochemistry. PD-progressive disease. PR: partial response. NA: non-applicable.
P01.033 Increased compliance with tumor treating fields is prognostic for improved survival in the treatment of glioblastoma: A subgroup analysis of the EF-14 phase III trial
Authors: Z Ram
Journal: Neuro-Oncology (2018)

Tumor Treating Fields (TTFields) are a physical anti-mitotic treatment modality characterized by their immediate mode of action and lack of a half-life. It has been shown that average monthly compliance with TTFields is correlated with overall survival in recurrent glioblastoma. Compliance ≥75% compliance (average daily use of at least 18h/d), has been suggested as a target for patients with recurrent glioblastoma receiving TTFields as monotherapy. In the EF-14 phase 3 trial in newly diagnosed glioblastoma, TTFields were applied together with temozolomide (TTFields/TMZ) and led to superior progression free (PFS) and overall survival (OS) compared to TMZ alone. We analyzed how rates of compliance with TTFields/TMZ correlated with PFS and OS in the EF-14 trial. Compliance was assessed using daily usage data from the NovoTTF-100A (Optune®) computerized log file. Compliance was calculated as percentage of 24-hour period of TTFields delivery. Patients on TTFields/TMZ were segregated into subgroups by percentage daily compliance: 0 - ≤30%; 30% - ≤50%; 50% - ≤60%; 60% - ≤70%; 70% - ≤80%; 80% - ≤90% and 90% - ≤100%. A Cox proportional hazard model controlled for sex, extent of resection, MGMT methylation status, age, region, and performance status was used to investigate the effect of compliance in PFS and OS. A threshold value of 50% average daily compliance with TTFields was needed to extend PFS (HR 0.70 95%CI 0.47–1.05) and OS (HR 0.67 95%CI 0.45–0.99) versus TMZ alone. A trend in favor of longer PFS and OS was seen with higher compliance subgroups (>90% compliance: PFS HR 0.54 95%CI 0.37–0.79; OS HR 0.52 95%CI 0.35–0.79). At compliance >90% median survival was 24.9 months (28.7 months from diagnosis) and 5-year survival was 29.3%. Compliance was independent of gender, extent of resection, MGMT methylation status, age, region and performance status (HR 0.78; p=0.031; for OS at compliance ≥75% vs <75%). A compliance threshold of 50% with TTFields/TMZ treatment correlated with significantly improved outcomes in OS and PFS versus TMZ alone. A trend in favor of longer PFS and OS was seen at higher compliance rates (90%). Increased compliance with TTFields therapy is prognostic for improved survival in glioblastoma.
Do risks with the use of erythropoeitin stimulating agents (ESAs) differ by tumor type? Implications concerning survival and thrombosis based on meta-analysis (MA).
Authors: Vineeth Sukrithan, Richard J. Gralla
Journal: Journal of Clinical Oncology (2016)

10023 Background: The use of ESAs in anemia associated with cancer remains controversial. Most studies analyzing ESAs have not estimated risks by tumor type, including the largest MA of 91 randomized clinical trials (RCTs) with 20,102 patients (pts) which again documented increased rates of thrombosis with decreased survival (Tonia et al, Cochrane Database of Systematic Reviews 2012). Given this large database, we proposed to analyze the results to determine if risks differed by tumor type. Methods: We conducted a MA including the RCTs in the 2012 Tonia MA, plus 3 more from a literature review. Inclusion criteria: RCTs comparing ESAs to placebo / control in specific solid tumor types. Trials with inadequate survival data were excluded. CMA software v3 (Biostat, NJ) was used to calculate combined thrombosis rates and survival ORs, using random effects models including heterogeneity testing. Sensitivity analyses by tumor type were performed. Results: A total of 34 RCTs with 9,808 pts were eligible and were analyzed. The risk of thrombosis (OR 1.93) was similar in each of four major tumor types; however, survival rates differed markedly by tumor type. In breast and in head and neck cancers, lower survival was seen. In lung cancer and in pelvic malignancies, no clear survival effect was found. Conclusions: We conclude: 1) nearly a doubling of thrombosis is found independent of the tumor type with ESA use; 2) the impact on survival differs by tumor type. These results indicate that survival detriments are not explained by thrombosis, in that this risk is equal in all cancers analyzed. These findings suggest that in certain cancers, ESAs may play a role in tumor promotion while in others ESAs may not have an activating role in tumor growth. RCTs (Patients) OR (95%CI) p Thrombosis Overall Effect 27 (8259) 1.93 (1.6-2.34) <0.01 Head and Neck 3 (794) 2.17 (0.89-5.3) 0.09 Breast 8 (4518) 1.94 (1.46-2.57) <0.01 Lung 7 (1747) 1.82 (1.35-2.48) <0.01 Pelvic 9 (1200) 2.24 (1.19-4.21) 0.01 Survival Overall Effect 32 (9692) 1.09 (0.98-1.2) 0.12 Head and Neck 5 (1397) 1.23 (0.98-1.53) 0.07 Breast 9 (4713) 1.20 (1.03-1.39) 0.02 Lung 10 (2417) 0.94 (0.73-1.2) 0.6 Pelvic 8 (1165) 1.06 (0.85-1.33) 0.6