bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of vemurafenib in patients (pts) with non-small cell lung cancer (NSCLC) with BRAFV600 mutation.
Authors: Subbiah Vivek , Gervais Radj , Riely Gregory J. , Hollebecque Antoine , Blay Jean-Yves , Felip Enriqueta , Schuler Martin H. , Goncalves Anthony , Italiano Antoine , Keedy Vicki Leigh , Chau Ian , Puzanov Igor , Raje Noopur , Makrutzki Martina , Riehl Todd , Pitcher Bethany , Hyman David Michael , Baselga Jose 
Published: September 2018

9074 Background: BRAFV600 mutations occur in 1–2% of pts with NSCLC. We previously reported the efficacy of vemurafenib, a selective BRAFV600 inhibitor, in BRAF mutation-positive non-melanoma tumors (VE-BASKET study). We now present final data for the expanded NSCLC cohort. Methods: This open-label, histology-independent, phase 2 study included 6 prespecified cohorts (including NSCLC) plus one ‘all-others’ cohort. Pts received vemurafenib (960 mg bid) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (RECIST v1.1). Secondary endpoints included best overall response rate, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Because the pre-specified clinical benefit endpoint was met in the initial NSCLC cohort, the cohort was expanded. ClinicalTrials.gov identifier NCT01524978. Results: Database lock was 12 Jan 2017. Of 208 pts enrolled at 25 centers worldwide, 62 pts had NSCLC: median age 65 years; 56% male; 13% had no prior systemic therapy; 50% had ≥2 prior therapies. Responses were seen in previously treated and untreated pts (Table). The most common all-grade adverse event (AE) was nausea (40%); grade 3–5 AEs included keratoacanthoma (15%) and squamous cell carcinoma of the skin (15%). Six pts discontinued vemurafenib due to AEs; two had non-treatment-related fatal AEs. Conclusions: Vemurafenib showed evidence of encouraging efficacy in pts with NSCLC with BRAFV600 mutation, with prolonged PFS in previously untreated pts; median OS was not estimable due to ongoing responses. The safety profile of vemurafenib was similar to that seen in melanoma studies. Our results suggest a role for BRAF inhibition in NSCLC with BRAF mutations. Clinical trial information: NCT01524978. [Table: see text]
Immune-related adverse events (IRAEs) in metastatic lung cancer patients receiving PD-1/PD-L1 inhibitors and thoracic radiotherapy.
Authors: Hwang William L. , Niemierko Andrzej , Willers Henning , Keane Florence K. , Gainor Justin F. 
Published: September 2018

9079 Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but are associated with unique IRAEs, including pneumonitis (PNS). Thoracic radiotherapy (TRT) is also associated with PNS but it is unknown whether TRT+ICI increases the risk of PNS or other IRAEs. Furthermore, low serum LDH levels are associated with better response/survival to ICI but its potential role as a biomarker for IRAEs is unexplored. Methods: We retrospectively reviewed 164 pts with metastatic lung cancer (95% NSCLC, 5% SCLC) consecutively treated at our institution from 2013-2016 with PD-1/PD-L1 inhibitors and a minimum of one month follow-up, except in cases of rapid death from an IRAE ( n =4). Pts were grouped according to TRT received (+ vs -). IRAE grades were assigned using NCI CTCAE v4.0. Outcomes were compared using Fisher’s exact test and two-sided Student’s t-test. Results: Baseline characteristics such as age, gender, smoking status, supplemental oxygen requirement, median number of chemotherapy lines prior to ICI (1 vs 1), median ICI cycles (5 vs 3), and median follow-up after ICI initiation (8 vs 7 months) were similar in the +TRT ( n = 73) and -TRT ( n =91) groups. Rates of grade ≥ 2 IRAEs (18.1 vs 14.4%, p = 0.67), all-grade PNS (8.2 vs 5.5%, p= 0.54), and grade ≥ 2 PNS (4.1 vs 3.3%, p = 1) were not significantly different between the +TRT and -TRT cohorts. Mean TRT dose was similar between those pts who developed PNS and those who did not (55.8 vs 55.9 Gy). In the +TRT group, 85% received TRT a median of 8.6 months before ICI. Among 7 pts (10%) who had concurrent TRT+ICI, none developed symptomatic PNS. Patients who developed grade ≥ 2 IRAEs ( n= 26) had significantly higher mean serum LDH before initiation of ICI than patients who did not (283 vs 214, ref 98-192 IU/L, p= 0.03). Conclusions: TRT in lung cancer pts receiving ICI was not associated with increased risk of PNS in this series. LDH may be a negative predictive biomarker as pts who suffered grade ≥ 2 IRAEs had significantly higher baseline LDH than those who did not. Larger cohorts and prospective studies would be helpful to validate these findings.
Use of PD-1 pathway inhibitors among patients with non-small cell lung cancer (NSCLC) and preexisting autoimmune disorders.
Authors: Leonardi Giulia Costanza , Gainor Justin F. , Azimi Roxana S. , Riess Jonathan , Rizvi Hira , Hellmann Matthew David , Awad Mark M. 
Published: September 2018

9081 Background: Since patients (pts) with NSCLC and autoimmune (AI) disease were largely excluded from immune checkpoint inhibitor clinical trials, we aimed to determine the safety of PD-1 inhibitors in NSCLC pts with a history of AI diseases. Methods: As part of a multi-center, retrospective study, we collected clinicopathologic data from pts with advanced stage IIIB or stage IV NSCLC with a history of AI disease and who received treatment with a PD-1 inhibitor as monotherapy. Qualifying AI disorders included but were not limited to: thyroiditis (excluding hypothyroidism without clear autoimmune etiology), inflammatory bowel disease, as well as rheumatologic, neurologic and dermatologic conditions. Results: We identified 46 pts with NSCLC treated with a PD-1 inhibitor who also had a history of AI disease. At the time of PD-1 inhibitor treatment initiation, 13% of pts had active AI symptoms and 19% were receiving immunomodulatory agents for their AI condition. The median period of follow up after initiation of anti-PD-1 therapy was 17.4 weeks (range 0.6-72.1 weeks). Exacerbation of the underlying AI condition occurred in 8 pts (17%). Two of these pts required steroid treatment (both for rheumatoid arthritis), and three of these pts required temporary interruption of treatment due AI disease flare. Overall, twelve (26%) pts developed at least one immune-related adverse event (irAE) unrelated to the underlying AI condition (8 grade 1-2, 4 grade 3); there were no cases of grade 4-5 irAEs. PD-1 therapy was permanently discontinued in 3 cases due to the development of an irAE (1 for grade 1 pneumonitis, 1 for grade 3 transaminitis, 1 for grade 3 diabetes insipidus). Conclusions: In pts with NSCLC and a history of AI conditions treated with PD-1 blockade, symptomatic flare of underlying AI disease was uncommon. The rate of immune-related toxicities in this population appears similar to published studies in pts without baseline AI conditions. Further analysis of pts with active AI conditions is needed to clarify the safety profile in this population.
Response to salvage chemotherapy following exposure to immune checkpoint inhibitors in patients with non-small cell lung cancer.
Authors: Leger Paul Denis , Rothschild Sasha , Castellanos Emily , Pillai Rathi Narayana , York Sally Jane , Horn Leora 
Published: September 2018

9084 Background: Immune checkpoint inhibitors are active for patients with stage IV NSCLC who have progressed following platinum-based chemotherapy. We evaluated responses to chemotherapy in patients who had progressed on a checkpoint inhibitor. Methods: Eligible patients were adults with NSCLC who received salvage chemotherapy following PD-1/PD-L1 inhibitors (cases) versus no PD-1/PD-L1 inhibitors (controls). CT-imaging was done within 4 weeks of initiation of salvage chemotherapy and every 6 weeks thereafter. Revised RECIST guidelines were used to define response. Clinical and imaging data were abstracted from review of electronic medical records. Multivariate logistic regression analysis was used to calculate probability of response. Results: Three-hundred and fifty patients’ charts were reviewed and 82 patients met eligibility criteria. Among evaluable patients, 46 were males. Sixty-seven patients were cases versus 15 controls. Fifty-six patients received nivolumab, 7 pembrolizumab and 4 atezolizumab. Sixty-three (77%) had adenocarcinoma, 18 (22%) squamous cell carcinoma and 1 (1%) large cell carcinoma. The mean number of chemotherapy regimens prior to salvage chemotherapy was 2.37 (95% C.I. 2.10-2.64)) in cases versus 1.93 (95% C.I: 1.32-2.54) in controls. Salvage drugs included docetaxel (62%), pemetrexed (20%), gemcitabine (12%), paclitaxel (6%). Eighteen (27%) cases had partial response to chemotherapy versus 1(7%) controls. Fifteen (22%) cases had progressive disease versus 6 (40%) controls. Thirty-four (51%) cases had stable disease versus 8 (53%) controls. The odd ratio for achieving a partial response was 0.30 (95% CI: 0.18 to 0.50, P = 0.000). In multiple logistic regression model, age, gender, number of prior chemotherapy regimens, tumor histology, smoking status, different salvage chemotherapy regimens were not associated with the likelihood of achieving a partial response. Conclusions: The odds of achieving a partial response to salvage chemotherapy were more than 3 times higher inpatients with prior exposure to PD-1/PD-L1 inhibitors. Ongoing investigations include the duration of response as well as evaluation of toxicity.
Efficacy, safety, and immune activation with pegylated human IL-10 (AM0010) in combination with an anti-PD1 in advanced NSCLC.
Authors: Wong Deborah Jean Lee , Schneider Jeffrey Gary , Aljumaily Raid , Korn Wolfgang Michael , Infante Jeffrey R. , Patel Manish R. , Autio Karen A. , Papadopoulos Kyriakos P. , Naing Aung , Gabrail Nashat Y. , Munster Pamela N. , Goldman Jonathan Wade , Van Vlasselaer Peter , Brown Gail Linda , Hung Annie , Oft Martin , Garon Edward B. 
Published: September 2018

9091 Background: Although IL-10 has anti-inflammatory properties, it stimulates cytotoxicity and proliferation of intratumoral antigen activated CD8+ T cell at higher concentrations. AM0010 is anticipated to activate antigen stimulated, intratumoral CD8 T cells while PD-1 inhibits them, providing the rationale for combining AM0010 and anti-PD-1 antibody. Methods: We treated a cohort of 34 NSCLC pts with AM0010 (10-20mg/kg QD, SC) and a PD-1 inhibitor [pembrolizumab (2mg/kg, q3wk IV; n=5) or nivolumab (3mg/kg, q2wk IV; n=29)]. Tumor responses were assessed by irRC every 8 weeks. Immune responses were measured by analysis of serum cytokines (Luminex), activation of blood derived T cells (FACS) and peripheral T cell clonality (TCR sequencing). Tumor PD-L1 expression was confirmed by IHC (22C3). Results: Pts had a median of 2 prior therapies. Median follow-up is 9.6 mo (range 0.5-77.3) in this fully enrolled cohort. AM0010 plus anti-PD-1 was well-tolerated. TrAEs were reversible and transient, with most being low grade, most commonly fatigue and pyrexia. G3/4 TrAEs were thrombocytopenia (7), anemia (6), fatigue (4), rash (3), pyrexia (2), hypertriglyceridemia (1) and pneumonitis (1). As of Jan. 31 2017, 22 pts had at least 1 tumor assessment. Partial responses (PRs) were observed in 8 pts (36.4%). 17 of these 22 pts had tissue for analysis of percent of tumor cells with PD-L1 expression (22C3): 58.8% had <1%, 17.7% had 1-49% and 23.5% had >50%. Best response data stratified for PD-L1 are shown in the table. Median PFS and OS for the entire cohort have not been reached. Updated outcome data that includes all enrolled pts will be available at the meeting. AM0010 plus anti-PD1 increased serum Th1 cytokines (IL-18, IFNγ), the number and proliferation of PD1+ Lag3+ activated CD8+ T cells and a de-novo oligoclonal expansion of T cell clones in the blood while decreasing TGFβ. Conclusions: AM0010 in combination with anti-PD1 is well-tolerated in advanced NSCLC pts. The efficacy and the observed CD8+ T cell activation is promising. Clinical trial information: NCT02009449. [Table: see text]
Nivolumab (N) plus ipilimumab (I) as first-line (1L) treatment for advanced (adv) NSCLC: 2-yr OS and long-term outcomes from CheckMate 012.
Authors: Goldman Jonathan Wade , Antonia Scott Joseph , Gettinger Scott N. , Borghaei Hossein , Brahmer Julie R. , Ready Neal E. , Gerber David E. , Chow Laura Q. , Juergens Rosalyn A. , Shepherd Frances A. , Laurie Scott Andrew , Geese William J. , Li Ang , Li Xuemei , Hellmann Matthew David 
Published: September 2018

9093 Background: The fully human anti–PD-1 antibody N offers long-term OS benefit in patients (pts) with previously treated adv NSCLC. Adding I (anti–CTLA-4 antibody) to N has been shown to improve clinical activity vs either agent alone in multiple tumor types. We present long-term data for 1L N+I treatment of pts with adv NSCLC from CheckMate 012. Methods: In two cohorts in this phase 1 study, pts with recurrent stage IIIb/IV, chemotherapy-naive NSCLC and ECOG PS 0–1 received N 3 mg/kg Q2W combined with I 1 mg/kg Q12W (n=38) or Q6W (n=39) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was safety and tolerability. Secondary endpoints included investigator-assessed ORR (RECIST v1.1) and PFS. Exploratory endpoints included OS and efficacy by tumor PD-L1 expression. Results: In the N+I Q12W and N+I Q6W cohorts, respectively, 42% and 31% of pts experienced grade 3–4 treatment-related (TR) AEs; 18% in each cohort discontinued due to any-grade TRAEs. The most frequently reported any-grade TRAEs were pruritus (26%) and diarrhea (21%) with N+I Q12W, and fatigue (26%) and diarrhea (23%) with N+I Q6W. There were no TR deaths. N+I showed promising efficacy (table). While efficacy was enhanced with increasing PD-L1 expression, activity was noted in pts with <1% PD-L1 (table). Of 6 complete responses (CRs), 3 were in pts with <1% PD-L1. Conclusions: 1L therapy with N+I demonstrates a manageable safety profile and promising, durable efficacy (including pathological CRs) in adv NSCLC; efficacy was enhanced in pts with ≥1% PD-L1 tumor expression. Longer follow-up data, including 2-yr OS and characteristics of long-term survivors, will be presented. Clinical trial information: NCT01454102. [Table: see text]
Adjuvant bevacizumab as treatment for melanoma patients at high risk of recurrence: Final results for the AVAST-M trial.
Authors: Corrie Philippa , Marshall Andrea , Lorigan Paul , Gore Martin Eric , Tahir Saad , Faust Guy , Kelly Charles G. , Marples Maria , Danson Sarah , Marshall Ernest , Houston Stephen , Board Ruth E. , Waterston Ashita Marie , Nobes Jenny Penelope , Harries Mark , Kumar Satish , Young Gemma , Barker Emily , Dunn Janet , Middleton Mark R. 
Published: September 2018

9501 Background: Bevacizumab (Bev) is a recombinant humanised monoclonal antibody to vascular endothelial growth factor (VEGF) shown to improve survival in several advanced solid tumours. As VEGF is a relevant target in melanoma, AVAST-M aimed to evaluate the role of Bev in melanoma patients at high risk of recurrence. Methods: AVAST-M (ISRCTN81261306) is a randomised phase III trial evaluating single agent Bev (7.5mg/kg IV 3 weekly for 1 year) as adjuvant therapy after resection of AJCC stage IIB, IIC and III cutaneous melanoma compared to standard observation (Obs). 1320 patients were needed to detect 8% differences in 5 year overall survival (OS) rate from 40% to 48%; 85% power, 5% alpha level. Primary endpoint was OS; secondary endpoints included disease free interval (DFI), distant-metastasis free interval (DMFI). BRAF and NRASmutation status were obtained in 682 patients in a translational sub-study. Results: From July 2007 to March 2012, 1343 patients were recruited (671 to Bev; 672 to Obs). 56% were male, median age was 56 years (range 18-88 years), 14% were stage IIIA and 59% were stage IIIB/C. With 6 years median follow-up, 505 (38%) patients had died (251 [37%] on Bev; 254 [38%] on Obs); 699 (52%) patients had recurred (335 [50%] on Bev, 369 [55%] on Obs). OS at 5 years was 64% on Bev versus 63% on Obs (Hazard ratio [HR] 0.99; 95% confidence interval [CI] 0.84-1.18, p=0.96). At 5 years, 51% were disease free on Bev versus 45% on Obs (HR 0.85; 95% CI 0.74-0.99, p=0.04) and 59% were distant metastasis free on Bev versus 54% on Obs (HR 0.91; 95% CI 0.77-1.07, p=0.24). A BRAF V600 mutation was found in 44% of tumours assessed; 20% were NRAS mutant. BRAF mutant patients treated with Bev tended to have better DFI (HR=0.79 95% CI 0.58-1.08, p=0.14) and OS (HR=0.79; 95% CI 0.55-1.13, p=0.20); this was not evident for BRAF WT. NRAS mutant patients tended to have worse DFI (HR=1.39; 95% CI 1.03-1.88; p=0.03) and OS (HR=1.18; 95% CI 0.85-1.62, p=0.20) than NRASWT patients. Conclusions: This large, multi-centre trial of melanoma patients at high risk of recurrence has shown that adjuvant Bev improves DFI, but this does not translate into an overall survival benefit. Funding:Cancer Research UK; drug supplied by Roche Products Ltd. Clinical trial information: ISRCTN81261306.
Final results of a phase II multicenter trial of HF10, a replication-competent HSV-1 oncolytic virus, and ipilimumab combination treatment in patients with stage IIIB-IV unresectable or metastatic melanoma.
Authors: Andtbacka Robert Hans Ingemar , Ross Merrick I. , Agarwala Sanjiv S. , Taylor Matthew H. , Vetto John T. , Neves Rogerio Izar , Daud Adil , Khong Hung T. , Ungerleider Richard S. , Tanaka Maki , Grossmann Kenneth F. 
Published: September 2018

9510 Background: HF10 is a bioselected replication-competent oncolytic virus derived from HSV-1. Herein, we report the safety and efficacy data of HF10 + ipilimumab (ipi) combination treatment in a Phase II trial in melanoma. Methods: Key entry criteria: age ≥ 18 yrs, ECOG ≤ 2, Stage IIIB, IIIC, or IV unresectable melanoma, ipi naïve (IV administration) and measurable non-visceral lesion(s) suitable for injection. HF10 injected into single or multiple tumors (1 x 107 TCID50/mL/dose, up to 5mL depending on tumor size and number); 4 injections q1wk; then up to 15 injections q3wk. Four ipi IV infusions (3 mg/kg; concurrent with HF10) were administered q3wk. AEs assessed per CTCAE 4.0. Tumor responses were assessed per mWHO and irRC at 12, 18, 24, 36 and 48 wks for patients (pts) continuing on HF10 monotherapy. Primary endpoint was Best Overall Response Rate (BORR) at 24 wks. Dose limiting toxicity (DLT) defined as ≥ G3 non-hematologic/hematologic toxicity, ≥ G2 neurologic toxicity, or allergic event occurring within 1st 3wks of therapy. Results: Of 46 pts enrolled and treated: 59% men, median age 67 yrs (range 28 to 91); disease stage 20% IIIB, 43% IIIC and 37% IV; 57% were treatment naïve and 43% with ≥ 1 prior cancer therapy for unresectable/metastatic melanoma. Most HF10-related AEs were ≤G2, similar to HF10 monotherapy. No DLTs were reported. 37% had ≥G3 AEs, the majority due to ipi. HF10-related ≥G3 AEs (n=3) were embolism, lymphedema, diarrhea, hypoglycemia, and groin pain. Of the 44 efficacy evaluable pts per irRC, BORR at 24 weeks was 41% (16% irCR and 25% irPR); disease stability rate was 68% (16% irCR, 25% irPR and 27% irSD). As of Feb 06, 2017, median PFS was 19 months and median overall survival was 21.8 months. Conclusions: The combination HF10 and ipilimumab treatment demonstrated a favorable benefit/risk profile and encouraging antitumor activity in pts with stage IIIB, IIIC, or IV unresectable or metastatic melanoma. Clinical trial information: NCT02272855.
Overall survival (OS) analysis from an expanded access program (EAP) of nivolumab (NIVO) in combination with ipilimumab (IPI) in patients with advanced melanoma (MEL).
Authors: Hogg David , Chapman Paul B. , Sznol Mario , Lao Christopher D. , Gonzalez Rene , Daniels Gregory A. , Smylie Michael , Kudchadkar Ragini Reiney , Thompson John A. , Sharfman William Howard , Atkins Michael B. , Pavlick Anna C. , Jiang Joel , Avila Alexandre , Demelo Sheena , Hodi F. Stephen 
Published: September 2018

9522 Background: NIVO (anti-PD-1) and IPI (anti-CTLA-4), alone and in combination, are approved for the treatment of MEL. Phase II and III trials showed improved efficacy for NIVO+IPI versus IPI alone, but with a higher frequency of adverse events (AEs). In the phase II CheckMate 069 trial, the 2-year OS rate was 63.8% for all patients (pts) in the NIVO+IPI group. We report the first OS analysis, as well as updated safety data, from a North American EAP of NIVO+IPI in pts with MEL (CheckMate 218; NCT02186249). Methods: CheckMate 218 included pts with MEL who could have progressed on other therapies, but were anti-CTLA-4 and anti-PD-1 treatment-naive. Pts received NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4, followed by NIVO 3 mg/kg Q2W until disease progression or a maximum of 48 weeks from the first monotherapy dose. We assessed OS in the US cohort (n = 580) and safety in all pts (n = 732). Pts were followed for a minimum of 1 year in the USA and 6 months in Canada. Results: Of 732 pts, 43% had a BRAFmutation, 84% stage IV MEL, 51% M1c disease, 31% LDH > ULN (9% LDH > 2x ULN), and 13% received ≥1 prior systemic therapy in the metastatic setting. All pts received a median of 3 doses each for NIVO (range: 1–4) and IPI (range: 0–4) in the induction phase; 34% of pts received at least 1 dose of NIVO maintenance. The 1- and 2-year OS rates were 78.6% (95% CI: 74.2–82.4) and 65.3% (95% CI: 56.1–73.0), respectively. AEs of any grade occurred in 717 pts (98%), with grade 3/4 AEs in 470 pts (64%). Immune-modulating medications were used to manage any grade AEs, including grade 1/2 skin and gastrointestinal AEs, in 538 of 717 pts (75%), and to manage grade 3/4 AEs in 279 of 470 pts (59%). The most common treatment-related AEs of any grade were diarrhea (39%), pruritus (26%), and an increase in aspartate aminotransferase level (23%). Treatment-related deaths in 2 pts were reported as drug-induced liver injury and myocardial infarction. Conclusions: In this EAP, which included pts who had received prior systemic therapies for MEL and pts with poor prognostic factors generally not included in clinical trials, NIVO+IPI treatment demonstrated survival outcomes and a safety profile consistent with clinical trial data. Clinical trial information: NCT02186249.