tbuckley/cabot-search huggingface dataset:
Association of baseline neutrophil-to-lymphocyte ratio (NLR) with response and survival in advanced melanoma (MEL) receiving PD-1 inhibitors.
Authors: Amit Hemadri, Huang Lin, Yan Lin, Amy Rose, Cindy Sander, Yana Najjar, Hassane M. Zarour, John M. Kirkwood, Diwakar Davar
Journal: Journal of Clinical Oncology (2019)

9571 Background: Inflammation is an adverse prognostic factor in cancer. Neutrophil-to-lymphocyte ratio (NLR) is an easily derived biomarker of systemic inflammation. Several studies have demonstrated that elevated NLR is linked with adverse prognosis in patients (pts) receiving immunotherapy including PD-1 inhibitors. To evaluate the prognostic utility of NLR, we performed a retrospective evaluation of NLR and other covariates in stage IV cutaneous MEL. Methods: Stage IV cutaneous MEL pts who received anti PD-1 therapy at the University of Pittsburgh between 2014-2018 were included in this analysis. PD-1 blockade was continued until progression or intolerable toxicity. Tumor assessment was performed at baseline and every 12 weeks and response classified per RECIST v1.1. Clinical and demographic data were obtained. Baseline NLR was defined based on values at the first treatment date. Descriptive statistics were created for all covariates. Kaplan Meier and Cox proportional hazard regression were performed to assess how variables related to response (ORR), overall survival (OS) and progression free survival (PFS) measured in months (mos). Results: 172 pts with advanced MEL were evaluated. Elevated NLR was associated with poorer PFS and OS and ORR at all cutoffs (NLR≥2 to NLR≥5) with NLR≥5 having the greatest discriminative value. ORR steadily declined with increasing NLR: NLR≥1 (ORR 64%), NLR≥2 (ORR 61%), NLR≥3 (ORR 52%), NLR≥4 (ORR 43%), NLR≥5 (ORR 43%). Elevated NLR ( &lt; 5 vs. ≥5) was associated with poorer PFS (median 21.5 mths vs. 5.2 mos; p = 0.00041) and OS (median 35.4 os vs. 10.6 mos; p &lt; 0.0001). In a multivariate model, elevated NLR ( &lt; 5 vs. ≥5) was independently associated with poorer OS/PFS separate from ulceration, performance status and elevated LDH. There was no evidence of an age-related increase or decrease in NLR. Conclusions: Baseline NLR was independently associated with response, PFS and OS in the largest retrospective series of advanced MEL pts treated with PD-1 blockade. NLR independent of other factors predicted poorer PFS and OS at NLR cutoffs (NLR≥3 to NLR≥5), although NLR≥5 segregated pts best. NLR is an inexpensive and easily obtained real-world biomarker that has a high value in predicting outcomes to PD-1 blockade.
Gastrointestinal, pancreatic, and hepatic toxicity profile of CTLA-4 immune checkpoint inhibitors alone and in combination with PD-1/PD-L1 inhibitors: A meta-analysis of clinical trials.
Authors: Faisal Ali, Maryam R Hussain, Aman Deep, Hamzah Abu-Sbeih, Taha Alrifai, Phyo Thazin Myint, Zimu Gong, Kelley Elizabeth Kozma
Journal: Journal of Clinical Oncology (2019)

e14117 Background: Cytotoxic T-lymphocyte activator-4 immune checkpoint inhibitors (CTLA-4-ICPI) is believed to cause more toxicity than programmed cell death/Ligand-1 (PD-1/PD-L1) ICPIs. We conducted a meta-analysis to outline the gastrointestinal (GI), pancreatic, and hepatic toxicity of CTLA-4 ICPIs when used alone and in combination with PD-1/PD-L1 ICPIs (C-ICPI). Methods: Ovid MEDLINE, EMBASE, Cochrane Library, SCOPUS, Web of Science, ClinicalTrials.gov, and WHO ICTRP were queried from January 2007-October 2018. Clinical trials reporting ICPI associated adverse events (AEs) were included. Colitis was defined as the development of diarrhea or documented colitis of any grade. Pancreatitis was defined as an elevation of amylase or lipase. Hepatitis was defined as elevation of ALT, AST, or transaminitis of any grade. A meta-analysis of proportions was conducted to report pooled AEs rate with 95% confidence intervals (CI) using a random effects model. Results: Overall, 30 study arms (20 CTLA-4, 10 C-ICPI) enrolling 3721 patients were included. There were a total of 3944 and 3317 AEs with CTLA-4 and C-ICPI use, respectively, with a pooled incidence of high grade AEs (grade 3-5; HAEs) of 23% (95% CI 16-33%) with CTLA-4 use and 52% (95% CI 37-67%) with C-ICPI use ( Table). The incidence of high-grade colitis was higher among patients treated with CTLA-4 ICPI. The proportion of high-grade pancreatitis was higher among patient who received C-ICPI. Two GI perforations were reported with CTLA-4 use. Pooled incidence of treatment related mortality was 1% in both groups. Conclusions: Though the overall GI, hepatic and pancreatic safety profile of CTLA-4 is comparable to C-ICPI, a higher incidence of high-grade colitis was found with CTLA-4. Two GI perforations were reported with CTLA-4 and warrant further investigation. No difference in treatment related mortality was found among the two groups. [Table: see text]
Tumor stroma percentage (TSP) and intrinsic subtypes in stage II/III colon cancer: NRG Oncology/NSABP C-07 trial.
Authors: Rim S Kim, Patrick G Gavin, Soonmyung Paik, Carmen Joseph Allegra, Samuel A. Jacobs, Katherine L. Pogue-Geile, Peter C. Lucas
Journal: Journal of Clinical Oncology (2019)

e15075 Background: Recent molecular subtype studies of colorectal cancer (CRC) have identified various genomic signatures. Regardless of the variety of studies, poor prognosis is associated with stem-like or mesenchymal subtypes, which are largely contributed by stromal cells or cancer-associated fibroblasts (CAF) and are driven by transforming growth factor-beta (TGF-ß) signaling. Tumor stroma percentage (TSP) in CRC morphologically evaluated on H&amp;E slides has been reported as an independent prognostic parameter in stage II/III colon cancer patients (pts). We tested the association of TSP with molecular subtypes in NRG Oncology/NSABP C-07, in which pts with a stem-like or mesenchymal subtype had a poor prognosis regardless of chemotherapy regimen. Methods: Ninety seven pts with available archived whole-section H&amp;E images from C-07 were reviewed for TSP for the stromal proportion in the most invasive part of the primary tumor as stroma-high (&gt;50%) or stroma-low (≤50%) as described in other studies. The population was selected to be enriched with stem-like subtype. Subtypes were determined by modified centroids based on Assigner (CRCA) classifier using archived nCounter data, described previously. Results: Of 23 pts, 22 (95.7%) with stroma-high tumor (TSP &gt;50%) were classified with the stem-like subtype. One stroma-high pt had a tumor with a non-stem-like subtype. Of 56 pts with stem-like subtype tumors, 22 were classified as stroma-high, whereas 1/41 with non-stem-like tumors was classified as stroma-high (P=0.00007). Conclusions: TSP is strongly associated with stem-like subtype of poor prognosis in stage II/III CRC and identifies a subset of stem-like subtype. Further study may reveal TSP as a simple biomarker for treatment resistance and potential therapies targeting stromal cells or CAF driven by TGF-ß signaling. SUPPORT: sanofi; U10CA180868, -180822, U24CA196067, PA DoH; NSABP. No. of samples with TSP &gt;50 according to CRCA subtypes. Clinical trial information: NCT00004931. [Table: see text]
Real-world evidence in the treatment of metastatic non-small cell lung cancer in a single institution of Colombia in the period August 2015 to August 2018.
Authors: Luis Eduardo Pino, Aylen Vanessa Ospina Serrano, Ivan Camilo Triana
Journal: Journal of Clinical Oncology (2019)

e18204 Background: In Colombia, lung cancer is the first cause of mortality. However, there is a large gap in terms of the information available regarding the characteristics and survival of these patients in the country. Methods: This is an observational, descriptive study of a cohort of patients with stage IV non-small cell lung carcinoma who initiated medical treatment at Fundación Santa Fe de Bogotá, a high complexity hospital. We analyzed clinical characteristics, oncogenic addiction expression, PDL1 expression, treatments, progression free survival (PFS), overall survival (OSm) and treatment related complications. Results: Twenty-six patients were included during the 3 years. The OSm for all the cohort was 19.6 months(m). In the group without PDL-1 expression and negative for oncogenic addiction that received treatment with chemotherapy the OSm was 16.9m and the PFS 9.6m. The OSm for the group with EGFR mutation that received target therapy was 24,7m and the PFS 13.11m. The patients with ALK rearrangement treated with target therapy had an OSm 17m and PFS 5m. The group with expression greater than 50% for PDL-1 that received only immunotherapy OSm was 9.5m and PFS 9m, and in the group with expression for PDL-1 between 1-49% the median OSm and PFS has not been reached. In relation with grade 3 toxicity, 7% of patients that received chemotherapy had kidney failure, 7% emesis and 15% hyporexia. Patients that received target therapy 9% had diarrhea and 9% hepatotoxicity. 9% of patients with bevacizumab presented bleeding and 8% of patients with immunotherapy had autoimmune colitis, in all these cases the medication was suspended. Hypothyroidism was the most frequent complication with the immunotherapy, and it was resolved with substitution therapy. Conclusions: Clinical characteristics and outcomes of this cohort were similar to other lung cancer patients series. Factors like cigarette, nutritional status and ECOG were no significant in the survival. 34,6% of patients had EGFR mutation and 7% had ALK rearrangements. Related to PDL1 we found 26% expresser patients. The highest OS and PFS was for the group with the EGFR mutation and for the group with PDL-1 expression between 1-49%.
Molecular profiling of melanoma brain metastases (MBM) compared to primary cutaneous melanoma (CM).
Authors: Gino Kim In, Kelsey Anne Poorman, Michelle Saul, Steven O'Day, Jeffrey M. Farma, Steven Daveluy, Anthony J. Olszanski, Michael S. Gordon, Jacob Stephen Thomas, Burton Larry Eisenberg, Lawrence E. Flaherty, Geoffrey Thomas Gibney, Michael B. Atkins, Ari M. Vanderwalde
Journal: Journal of Clinical Oncology (2019)

9565 Background: Nearly 50% of metastatic melanoma patients develop brain metastases, warranting further investigation into the biology of this event. Methods: We analyzed 132 MBM and 745 CM submitted to Caris Life Sciences from 2015-2018, using next generation sequencing of a 44 or 592 cancer-related gene panel, tumor mutational burden (TMB), and PD-L1 expression by IHC. Genomic alterations (GA), including somatic mutations or CNA, were reported. High TMB (TMB-H) was defined as ≥17 mut/Mb. Comparison of molecular profiles, including cancer-related genes and recurrently altered pathways, between tumor sites and by genomic subgroup (BRAF, NRAS, KIT, NF1), was performed using Fisher’s exact test. Results: Among 132 MBM, 72.7% were male, with median age 62 yo (range 25-83). The most common GAs among MBM were: BRAF (52.4%), NRAS (26.6%), CDKN2A (23.3%), NF1 (18.9%), TP53 (18%), ARID2 (13.8%), SETD2 (11.9%), and PBRM1 (7.5%). Compared to CM, MBM were more often TMB-H (53.7% v 38%, p = .025), with higher PD-L1 expression, using both a ≥1% (54.4% v 35.6%, p = .002) and ≥5% cut-off (32.9% v 15.9%, p = .0006). MBM showed higher rates of GAs among: SETD2 (11.9% v 1.9%, p = .0008), BRAF (52.4% v 35.6%, p = .017), PBRM1 (7.5% v 1.6%, p = .018), KRAS (4% v 1%, p = .026), CCND1 (2.9% v 0%, p = .03), and DICER1 (4.4% v 0.6%, p = .04), compared to CM. Alterations of the MAPK (87.9% v 77.8%, p = .015) and SWI/SNF (22.1% v 11.6%, p = .036) pathway were more frequent in MBM, than CM. When analyzed by genomic subgroup, BRAF+ MBM had more GAs involving the PI3K pathway (20% v 5.1%, p = .027), compared to BRAF WT MBM. NRAS+ MBM had higher PD-L1 expression at the ≥1% cutoff (66.7% v 38.6%, p = .05), but not ≥5%, compared to NRAS WT MBM. NF1+ MBM had more GAs involving the SWI/SNF (60% v 11.6%, p = .003) pathway, as opposed to NF1 WT MBM. No significant associations were seen between KIT status, TMB, PD-L1 or other pathways among MBM. Conclusions: In this cross-sectional study, MBM demonstrated higher PD-L1 expression and were more often TMB-H, compared to CM. MBM also featured more GAs involving BRAF and the MAPK pathway. We identified two novel genes, PBRM1 and SETD2, as well as recurrent alterations of the SWI/SNF pathway, supporting future studies of chromatin remodeling pathways in MBM.
The anti–PD-1 antibody spartalizumab (S) in combination with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced <i>BRAF</i> V600–mutant melanoma: Updated efficacy and safety from parts 1 and 2 of COMBI-i.
Authors: Georgina V. Long, Celeste Lebbe, Victoria Atkinson, Mario Mandalà, Paul D. Nathan, ANA Maria Arance Fernandez, Erika Richtig, Naoya Yamazaki, Caroline Robert, Dirk Schadendorf, Hussein Abdul-Hassan Tawbi, Paolo Antonio Ascierto, Antoni Ribas, Keith Flaherty, Dung-Yang Lee, Aisha Masood, Eduard Gasal, Reinhard Dummer
Journal: Journal of Clinical Oncology (2019)

9531 Background: Checkpoint inhibitors and targeted therapies have improved outcomes in pts with BRAF V600–mutant advanced melanoma; however, many pts progress and new treatment (tx) strategies are needed. BRAF inhibition increases T-cell infiltration, melanoma antigen expression, and PD-1/PD-L1 expression, which may lead to synergistic activity with anti–PD-1 therapy. Methods: COMBI-i is investigating first-line S 400 mg Q4W + D 150 mg BID + T 2 mg QD in pts with unresectable or metastatic BRAF V600–mutant melanoma (NCT02967692). Here we report pooled efficacy and safety data from parts 1 (run-in cohort) and 2 (biomarker cohort). Response was assessed per RECIST v1.1. Results: 36 pts were enrolled (part 1: n = 9; part 2: n = 27); 18 (50%) had stage IV M1c and 15 (42%) had elevated LDH levels. At the data cutoff (median follow-up, 15.2 mo), tx was ongoing in 17 pts (47%). The confirmed objective response rate (ORR) by investigator assessment was 75% (n = 27), with 33% complete responses (CRs; n = 12). Medians for duration of response (DOR; 7/27 pts with events), progression-free survival (PFS; 13/36 pts with events), and overall survival (OS; 7/36 pts with events) were not reached. 12-mo DOR rate was 71.4% (95% CI, 49%-85%). 12-mo PFS and OS rates were 65.3% (95% CI, 47%-79%) and 85.9% (95% CI, 69%-94%), respectively. In pts with high baseline LDH: ORR was 67%, with 3 CRs (20%), median PFS was 10.7 mo (events in 10/15 pts [67%]), and median OS was not reached, with events in 6/15 pts (40%). All pts had ≥ 1 AE; 27 (75%) had grade ≥ 3 AEs. 6 pts (17%) had AEs leading to discontinuation of all 3 study drugs. Any-grade AEs in ≥ 40% of pts included pyrexia, chills, fatigue, cough, and arthralgia. Grade ≥ 3 AEs in &gt; 3 pts were neutropenia, pyrexia, and increased lipase. One pt died of cardiac arrest that was not considered related to study tx. Conclusions: S+D+T showed promising and durable ORR (75%) with CR in 33% of pts. With &gt; 15 mo of follow-up, median PFS was not reached. The safety profile was manageable reflecting individual toxicities of D, T, and S. The global, placebo-controlled, randomized phase 3 (part 3) of COMBI-i is ongoing. Clinical trial information: NCT02967692.
New model of care for patients with central nervous system cancers.
Authors: Elena Pentsova, Kathryn Sara Nevel, Franchesca Konig, Maryann Sibilla, Anna Skakodub, Malbora Manne, Mimma Errante, Milagros Gordilo, Gayle Rawlins-Peters, Dominique Jean-Charles, Anastasia Zankowsky, Jody Gilman, Brian Kelly, Stephanie Zavolas, Hannah Goldman, Grigory Syrkin, Eli L. Diamond, Lisa Marie DeAngelis, Lisa Marie Ruppert, Alan Carver
Journal: Journal of Clinical Oncology (2019)

87 Background: Patients (pts) with primary or metastatic central nervous system (CNS) cancers often have multiple physical, psychosocial, and spiritual needs. Likewise, neurological impairments can transform pts’ relationship dynamics with caregivers. These issues, along with prognosis and end of care planning, are difficult to address within a single outpatient oncology clinic. Methods: The Neurological Multidisciplinary Care Clinic (MdCC) at Memorial Sloan Kettering Cancer Center was a pilot study from 8/2017 to 6/2019 to foster a new model of care for complex pts with CNS cancers to identify and address their needs. Twice a month between 8/2017- 6/2019, a team comprised of a neurologist, nurse, physiatrist (RM), physical therapist, social worker (SW), case manager (CM), dietitian (RD), and chaplain (C) saw patients with neurological deficits and KPS ≤80. Within a 3 hour-visit, providers rotated in to see patients and their caregivers. Since 11/2017 participants completed validated surveys on unmet needs, financial strain, and home equipment prior to their visit, and satisfaction surveys afterward. Descriptive statistics were used to analyze results. Results: Eighty-two pts with advanced cancer were seen: 40 were female, median age 59. Of these 82 pts, 66 had primary CNS cancers, predominantly high-grade glioma/glioblastoma (79%). Over 60% had never seen a CM, RM, RD or C prior to MdCC. Seventy-eight pts (95%) received symptom management recommendations. Prognosis/coping with cancer was discussed with 75 pts (91%) which increased signed health care proxy forms by 16% and DNR orders by 6% at time or within a month post-MdCC. New/updated physical therapy was ordered for 50 pts (61%), orthotics for 10 (12%), and new equipment for 14 (17%). Forty-nine pts completed a satisfaction survey: of these, 96% were highly satisfied, and would recommend MdCC to others. Conclusions: Pts’/caregivers’ unmet needs were effectively identified and addressed within a single MdCC visit. The presence of several providers through MdCC allows for the assessment of pts’/caregivers’ needs and coping skills in real time. The MdCC also facilitates discussing pts’ goals of care, assessing their support system, and implementing a safe patient-centered plan of care.
Prospective phase I multi-institutional trial of PD-1 blockade with pembrolizumab during concurrent chemoradiation for locally advanced, unresectable non-small cell lung cancer.
Authors: Salma K. Jabbour, Abigail T. Berman, Roy H. Decker, Yong Lin, Steven J. Feigenberg, Scott N. Gettinger, Charu Aggarwal, Corey J. Langer, Charles B. Simone, Jeffrey D. Bradley, Joseph Aisner, Jyoti Malhotra
Journal: Journal of Clinical Oncology (2019)

8511 Background: The PACIFIC study showed that consolidative Programmed Death Ligand 1 inhibition (PD-L1i) after chemoradiation therapy (CRT) improves PFS and OS in patients with Stage IIII NSCLC (Antonia et al. NEJM 2017, 2018). Limited data, however, exist regarding the incorporation of PD-L1i concurrently during CRT. We sought to assess the safety and toxicity of PD-1i using pembrolizumab (pembro) during definitive CRT for Stage III NSCLC. Methods: In this multi-center prospective Phase I clinical trial using a 3+3 design, we evaluated the timing and dosing of pembro combined with chemotherapy (carboplatin + paclitaxel weekly) and definitive RT (60 Gy in 2 Gy/day x 30 fractions) for unresectable, locally advanced Stage III NSCLC (AJCC 7 th Ed). Dose Cohorts (C) evaluated were--C1: full dose (FD) pembro (200 mg IV Q3 weeks) 2-6 weeks after CRT; C2: reduced dose (RD) pembro (100 mg IV Q3 weeks) starting Day 29 of CRT; C3: FD pembro starting Day 29 of CRT; C4: RD pembro starting on Day 1 of CRT; C5: FD pembro starting on Day 1 of CRT. For each cohort, pembro was continued Q3 weeks for up to 18 cycles (as monotherapy after CRT in either RD or FD based on initial dose assignment). Dose Limiting Toxicity (DLT) was defined as Grade ≥4 pneumonitis within 21 days of cycle 1 of pembro. Results: We enrolled 23 subjects from 8/2016-11/2018; median follow up (f/u) was 11.4 mo (range, 3.1 mo- 25.2 mo). Median age was 69 yrs (range 53-85); 52% were women. No DLTs were observed in any of the cohorts (C1 to C5). Grade ≥3 immune-related adverse events (irAE) occurred in 4 patients (18%). irAE’s included: Grade 5 (bilateral), 3, 2 pneumonitis (n=1, 1, 4, respectively (6 total)); Grade 3 hyperglycemia (n=1); Grade 3 interstitial nephritis (n=1); Grade 2 thyroiditis (n=4); Grade 2 myositis (n=1); Grade 1-2 transaminitis (n=3). Median PFS for patients who received ≥2 doses (n=18) of pembro was 20.3 mo. Conclusions: Combined treatment with PD-Li and CRT for stage III NSCLC was well tolerated with promising PFS to date but showed an increased risk for irAEs, particularly pneumonitis. Based on these encouraging results, further prospective study of PD-1i and CRT for Stage III NSCLC is warranted. Clinical trial information: NCT02621398.
Do genetic testing criteria identify individuals with Lynch syndrome prior to cancer diagnoses?
Authors: Brian Reys, Caitlin Mauer, Sara Pirzadeh-Miller, Theodora S. Ross
Journal: Journal of Clinical Oncology (2019)

e13158 Background: Screening colonoscopies every 1-2 years are estimated to decrease the risk for colorectal cancer (CRC) development in individuals with Lynch syndrome (LS) by 62-72%. However, in order for risk reduction to be effective, genetic testing guidelines must identify individuals with LS before they develop CRC. Current NCCN indications for LS evaluation focus on individuals who have already developed cancer. This study aims to identify the effectiveness of NCCN criteria in identifying LS patients before a cancer develops. Methods: A retrospective chart review was performed for 173 patients with a personal history of a LS-associated cancer seen at UT Southwestern and affiliate hospitals between 2009-2018. All patients tested positive (pathogenic or likely pathogenic) for a LS-associated mutation. Review determined if patients met NCCN (v1.2018) criteria for the evaluation of LS before and after their personal diagnosis of cancer. The study controlled for known mutations in families, past iterations of NCCN guidelines and instances of limited family history. Results: Of patients with LS, 31.8% (55/173) met NCCN testing criteria only after their personal diagnosis of cancer. Data per gene reveals 13.3% (8/60) MLH1, 25.4% (16/63) MSH2, 44.8% (13/29) MSH6 and 85.7% (18/21) PMS2 mutation carriers in the cohort were missed by current guidelines . Conclusions: 31.8% of patients with LS mutations would not have met NCCN LS evaluation criteria prior to their diagnosis of cancer. Criteria disproportionately missed individuals with lower penetrant MSH6/PMS2 mutations. These findings highlight a need for the field to develop criteria that support the detection of LS in individuals with and without cancer. As the field debates the merits of population based testing, this study suggests the current criteria for LS germline testing are not sufficient for identification of LS prior to cancer diagnosis for many patients with LS.