julilili42/papers huggingface dataset:
Overall survival in COLUMBUS: A phase 3 trial of encorafenib (ENCO) plus binimetinib (BINI) vs vemurafenib (VEM) or enco in BRAF-mutant melanoma.
2018-05-20

9504 Background: Combined BRAF/MEK inhibitor therapy is standard of care in advanced BRAFV600-mutant melanoma. COLUMBUS Part 1 evaluated ENCO 450 mg once daily (QD) + BINI 45 mg twice daily (BID;COMBO450) vs VEM 960 mg BID or ENCO 300 mg QD (ENCO300) in patients (pts) with advanced BRAFV600-mutant melanoma. The primary study endpoint was progression-free survival (PFS); median PFS was 14.9 vs 7.3 mo for COMBO450 vs VEM; hazard ratio (HR): 0.54 (2-sided P< 0.001). Here we report a planned analysis of overall survival (OS), a secondary endpoint of the study. Methods: Pts with advanced/metastatic BRAFV600-mutant melanoma, untreated or progressed on/after first-line immunotherapy, were stratified by disease stage, Eastern Cooperative Oncology Group Performance Status and prior first-line immunotherapy. Pts in Part 1 were randomized 1:1:1 to COMBO450 (n = 192), ENCO300 (n = 194), or VEM (n = 191). Tumor responses and progression were assessed by blinded independent central review. An analysis of OS was planned after 232 events in the COMBO450 and VEM arms combined. Results: As of data cutoff,105, 106, and 127 events contributed to the OS analysis in the COMBO450, ENCO300, and VEM arms, respectively; median follow-up across arms was 21.5 mo. Median OS was 33.6 mo (95% CI, 24.4-39.2) with COMBO450, 23.5 mo (95% CI, 19.6-33.6) with ENCO300, and 16.9 mo (95% CI, 14.0-24.5) with VEM. Risk of death was reduced with COMBO450 vs VEM (HR, 0.61 [95% CI, 0.47-0.79]; nominal 2-sided P< 0.001). Updated median PFS was 14.9 mo (95% CI, 11.0–20.2) with COMBO450, 9.6 mo (95% CI, 7.4–14.8) with ENCO300, and 7.3 mo (95% CI, 5.6–7.9) with VEM. PFS was longer with COMBO450 vs VEM (HR, 0.51 [95% CI, 0.39–0.67]). Updated response rates, safety data, and information on 2nd-line therapy will be presented at the meeting. Conclusions: The best-in-class median PFS of 14.9 and median OS of 33.6 mo suggest that COMBO450 is a promising new regimen for treatment of BRAF-mutant melanoma. SPONSOR: Array BioPharma Inc. Clinical trial information: NCT01909453.
Pooled analysis of two randomized phase III trials (PlanB/SuccessC) comparing six cycles of docetaxel and cyclophosphamide to sequential anthracycline taxane chemotherapy in patients with intermediate and high risk HER2-negative early breast cancer (n=5,923).
2018-05-20

522 Background: Recent studies draw different conclusions concerning whether omission of anthracyclines (A) in adjuvant chemotherapy for HER2-negative early breast cancer (EBC) may reduce toxicity without compromising efficacy. Methods: The prospectively randomized PlanB and Success C trials compared 6 cycles of docetaxel (D) and cyclophosphamide (C) with either 4 cycles of epirubicin (E) and C, followed by 4 cycles of D (EC-D, PlanB) or 3 cycles of 5-FU, E and C, followed by 3 cycles of D (FEC-D, SuccessC). Disease-free survival (DFS) was analyzed using univariable and multivariable Cox models adjusted for hormone receptor status (HRS) and histologic grade (G), age, menopausal status, type of surgery, pT, pN, and histologic type. Results: Overall, 5923 patients with follow-up data were available for this pooled analysis, with 2979 and 2944 patients randomized to A-free and A-containing chemotherapy, respectively. After 62 months median follow-up, DFS of patients receiving A-free vs A-containing chemotherapy was quite similar in univariable analysis (hazard ratio, HR = 1.04; 95% confidence interval, CI: 0.88 – 1.22, p = 0.64) and in multivariable analysis (HR = 1.00, 95% CI: 0.85 – 1.19, p = 0.96). Defining biological subtypes “luminal A-like” as HRS positive, G1/2, “luminal B-like” as HRS positive, G3, and TN (triple negative), no significant differences were seen in DFS between A-free and A-containing chemotherapy in luminal A-like (HR = 1.06, 95% CI 0.81 – 1.39, p = 0.66), luminal B-like (HR = 1.07, 95% CI 0.78 – 1.48, p = 0.68), or TN tumors (HR = 0.99, 95% CI 0.76 – 1.30, p = 0.95). However, in high-risk patients with four or more affected lymph nodes (pN2-3), A-containing chemotherapy was associated with significantly better DFS (HR = 0.69, 95%-CI 0.48- 0.98, p = 0.04). Conclusions: Our results suggest that 6 cycles of DC provide sufficient efficacy compared to an anthracycline-containing regimen in most patients with HER2-negative EBC. However, subgroup analyses indicate that high-risk patients might benefit from anthracycline-containing chemotherapy.
Efficacy and safety of cobimetinib (C) combined with vemurafenib (V) in patients (pts) with BRAFV600 mutation–positive metastatic melanoma: analysis from the 4-year extended follow-up of the phase 3 coBRIM study.
2018-05-20

9522 Background: The coBRIM study demonstrated that first-line C+V improved progression-free (PFS) and overall survival (OS) compared with placebo (P)+V in pts with BRAFV600-mutated advanced melanoma. We report updated survival outcomes and safety after extended follow-up. Methods: coBRIM was a double-blind, multicenter study in which 495 patients were randomized to receive C (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle; n = 247) or P (n = 248) in combination with V (960 mg twice daily). PFS and OS were primary and secondary endpoints, respectively. Results: At database closure, median follow-up duration for the overall intent-to-treat population was 18.6 months (range, 0.5–55.1 months); 176 pts (71%) in the C+V arm and 190 pts (77%) in the P+V arm had discontinued the study, with the most common reason being death (C+V = 148 pts [60%]; P+V = 162 pts [65%]). Median PFS among pts receiving C+V was 12.6 months (95% confidence interval [CI], 9.5–14.7 months) vs 7.2 months (95% CI, 5.6–7.5 months) in pts receiving P+V. Median OS among pts receiving C+V was 22.5 months (95% CI, 20.3–28.8 months) vs 17.4 months (95% CI, 15.2–20.5 months) in pts receiving P+V. A greater proportion of pts receiving C+V were alive at 1, 2, 3 and 4 years vs pts receiving P+V (Table). Median duration of treatment in the C+V arm was 9.0 months (range, 0.1–53.1 months) for C and 9.2 months (range, 0.3–53.3 months) for V. Pts in the P+V arm had a shorter median duration of treatment of 5.6 months (range, 0.2–43.9 months) for P and 5.7 months (0.2–53.2 months) for V. Grade 3/4 adverse events (AEs) were reported in 75% and 61% of pts in the C+V and P+V arms, respectively. Grade 5 AEs were reported in 2% of pts in each study arm. A larger proportion of pts discontinued C+V (19%) versus P+V (10%) due to AEs. Conclusions: Extended follow-up of the phase 3 coBRIM study confirmed the survival benefit of C+V over P+V. No new safety signals were observed. Clinical trial information: NCT01689519. Landmark OS, % (95% CI) C+V P+V 1-year 74.5 (68.9–80.1) 63.8 (57.6–70.0) 2-year 49.0 (42.5–55.6) 39.0 (32.7–45.4) 3-year 38.5 (32.1–44.9) 31.1 (25.0–37.2) 4-year 34.7 (28.4–41.0) 29.2 (23.1–35.2)
GAPVAC-101: First-in-human trial of a highly personalized peptide vaccination approach for patients with newly diagnosed glioblastoma.
2018-05-20

2000 Background: The need for treatment personalization is obvious as every cancer is molecularly unique. In addition glioblastoma (GB) are immunologically regarded as resistant, "cold" tumor with few targetable antigens available from mutations, thus demanding new personalized immunotherapies. Methods: The GAPVAC consortium realized an immunotherapy, for which personalized selection of 2 peptide-based actively personalized vaccines (APVAC) per patient for treatment of newly diagnosed GB was based not only on whole-exome sequencing but also on human leukocyte antigen (HLA)-ligandome analyses providing insight into the actual presentation of relevant epitopes in the tumor. GAPVAC-101 (NCT02149225) enrolled 16 patients in a European phase I feasibility, safety and immunogenicity trial integrated into standard of care. For APVAC1, up to 7 peptides were selected from a trial specific warehouse based on individual biomarker data. Vaccination (i.d.) with GM-CSF and poly-ICLC in 15 patients started with the 1st adjuvant cycle of temozolomide (TMZ). For APVAC2, analyses revealed a median of 36 somatic, non-synonymous mutations in the patients' tumors. From the 4th TMZ cycle, 11 patients received APVAC2 with usually 2 de novo antigens per patient selected according to mutation, actual or putative HLA presentation and immunogenicity. Overall 20 APVAC2 antigens incl. 14 mutated were vaccinated. Results: Adverse events were largely reversible injection site reactions but also 2 anaphylactic reactions and one increase in cerebral edema. Short, non-mutated APVAC1 antigens induced sustained CD8 responses with memory phenotype, being with regard to CD8 immunogenicity rate (51%, ex vivo readout) numerically at least not inferior to long mutated antigens (45%, readout after in vitro culture). Mutated APVAC2 antigens induced predominantly CD4 responses of favorable TH1 type. Median PFS and OS were 14.2 and 29 months from diagnosis, respectively, in patients that received ≥1 APVAC vaccination (N = 15). Conclusions: Overall, the GAPVAC approach displayed expected safety profiles and high biological activity warranting further development. Clinical trial information: NCT02149225.
A mutation-specific peptide vaccine targeting IDH1R132H in patients with newly diagnosed malignant astrocytomas: A first-in-man multicenter phase I clinical trial of the German Neurooncology Working Group (NOA-16).
2018-05-20

2001 Background: Hot-spot point mutations in the gene for isocitrate dehydrogenase type 1 (IDH1R132H) are a frequent founder event in gliomas and other tumors. Preclinical studies have defined IDH1R132H as a clonal neoantigen presented on MHC class II to induce tumor-specific therapeutic T helper cell responses. Methods: NOA-16 (NCT02454634) is a first-in-man, multicenter, phase I trial, which enrolled 33 patients with newly diagnosed WHO °III and °IV astrocytomas with IDH1R132H mutations. After completion of radiochemotherapy a total of eight vaccinations with an IDH1R132H peptide in incomplete Freund's adjuvant produced at a central GMP site was to be administered subcutaneously with topical imiquimod over a period of 32 weeks together with maintenance temozolomide. The primary end points were safety and immunogenicity. Results: The safety dataset comprised 249 vaccines administered to 32 patients. One patient withdrew after screening. 29 patients received all eight vaccines. Vaccine-related adverse events (AE) were restricted to grade 1 reactions, according to common toxicity criteria for AE(CTCAE v4.0). Two serious AE were observed in two patients; one probably related to the peptide vaccine. 28/30 patients (93.3%) evaluable for immunogenicity displayed IDH1R132H-specific T cellular (detected by ELISPOT assays in 24/30 (80%)) or humoral (detected by ELISA in 26/30 patients (87%)) immune responses not detectable before vaccination. Until end of study (EOS, week 32), 4/32 (12.5 %) patients had progressive disease (PD) according to RANO criteria, all other patients (N = 28, 87.5%) had stable disease (SD). 12/32 (37.5%) patients displayed pseudoprogressions. Single-cell T cell receptor (TCR) sequencing allowed for the identification of IDH1R132H-specific TCRs. Conclusions: NOA-16 met its primary endpoints by demonstrating safety and immunogenicity of a mutation-specific IDH1R132H peptide vaccine. Pseudoprogressions observed after the initiation of the vaccine may indicate intratumoral immune reactions warranting further development, including TCR cell therapy. Clinical trial information: NCT02454634.
Final analysis of DECOG-SLT trial: Survival outcomes of complete lymph node dissection in melanoma patients with positive sentinel node.
2018-05-20

9501 Background: The multicenter DeCOG-SLT trial assessed in a randomized phase 3 trial whether complete lymph node dissection (CLND) resulted in increased survival compared with observation in patients with positive sentinel node biopsy (SLNB). This study now gives an update three years after inclusion of the last patient. Methods: Outcomes of 473 patients in the intent-to-treat population (ITT) randomly assigned into the DeCOG trial were evaluated with an additional 3 years follow-up observation after randomization has ended. A total of 233 patients was analyzed in the observation group, 240 in the CLND group. The primary endpoint was distant metastasis-free survival (DMFS); recurrence-free (RFS) and overall (OS) survival were secondary endpoints. Results: Patient enrolment was performed from January 2006 to December 2014 followed by an observation period from January 2015 to December 2017. The median follow-up time was 72 months (95% CI 67.2;76.8) No significant treatment-related difference was seen in the 5-years DMFS: 68% (90%CI: 62.1%;72.5%, 79 events) in the observation arm and 65% (90%CI: 59.3%;70.5%, 85 events) in the CLND arm (HR1.08 (90%CI 0.83; 1.39), P = 0.65). The 5 years RFS (HR 1.01 (90%CI 0.8; 1.28), P = 0.94) and OS (HR 0.99 (90%CI 0.74; 1.31), P = 0.93), also showed no differences with respect to the treatment arms. The 5-year DMFS differed according to the tumor load in the SLNB, but again not between CLND and observation arm (≤ 1.0 mm: 78.7% vs 72.5%, HR 1.12, P = 0.58 and > 1.0 mm 54.7% vs 51.7%, HR 0.98, P = 0.95) Regional lymph node metastases occurred in 10.8% of the CLND and in 16.3% of the observation arm (P = 0.11) The multivariate proportional hazard regression analysis revealed tumor thickness and tumor load in the SLNB to be independent prognostic factors for RFS, DMFS and OS. Conclusions: After a median follow-up time of 72 months there was no survival benefit in melanoma patients with positive SLNB undergoing CLND compared to observation only. Clinical trial information: NCT02434107.
Pomalidomide (POM), bortezomib, and low‐dose dexamethasone (PVd) vs bortezomib and low-dose dexamethasone (Vd) in lenalidomide (LEN)-exposed patients (pts) with relapsed or refractory multiple myeloma (RRMM): Phase 3 OPTIMISMM trial.
2018-05-20

8001Background: POM, a standard-of-care treatment (Tx) in RRMM, has demonstrated synergistic anti-myeloma activity with dexamethasone (DEX) and proteasome inhibitors (PIs). POM + DEX is indicated f...
The utility of chemotherapy after immunotherapy failure in metastatic melanoma: A multicenter case series.
2018-05-20

e21588 Background: Immune checkpoint inhibitors are standard of care for most patients (pts) with MM, yet only a minority has durable disease control. CTX has limited activity when used first-line, but can alter the tumor microenvironment and has improved efficacy when used in combination with IT in lung cancer. Whether CTX given after IT failure has clinically significant activity in MM pts is unknown. Methods: Consecutive MM pts treated with CTX after failing IT were retrospectively identified from 24 melanoma centers. Primary endpoints were RECIST objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: 463 pts were treated with CTX between 2007 and 2017. Prior IT included ipilimumab (44%), PD1 antibodies (44%), and combination immunotherapies (12%). 37% had 2+ lines of IT, and 42% had received PD1 antibodies just prior to CTX. The median interval between IT and CTX was 1.9 months (0 - 40.8). At start of CTX, median age was 58y, 86% were stage M1c, 57% had elevated LDH, and 58% had ECOG > 1. CTX included carboplatin + paclitaxel (C+P, 32%), dacarbazine (DTIC, 25%), temozolomide (TMZ, 15%), taxanes (9%), fotemustine (FOT, 6%), and others (13%). Median (med) duration of therapy was 7.9 weeks (0 - 108). No unexpected toxicities were observed. In the whole cohort, 0.4% had CR, 12% PR, 21% SD and 65% PD. Med PFS was 2.7 months (2.4, 3.0), and median PFS in responders was 8.7 months (6.3, 16.3). In pts who had received anti-PD1 prior to CTX, the ORR was 11%, and med PFS 2.5 months (2.1, 2.8). Best activity was achieved with taxanes (N = 41), with ORR 27% and med PFS 3.9 months (2.1, 6.2). ORR for other regimens included C+P (14%), FOT (11%), DTIC (10%), TMZ (3%). 48% of patients had further therapy after CTX, including PD1 in 59%. Med OS from CTX start was 7.1 months (6.5, 8.0); 16.8 months (13.0, 40.6) in CTX responders and 6.5 months (5.9, 7.5) in non-responders (p < 0.0001). Conclusions: Overall, CTX had low response rate and short PFS in MM pts who have failed IT, although activity varied between regimens. Additional analyses are ongoing to identify predictors of clinical benefit with CTX in this setting.
Randomized comparison of pazopanib (PAZ) and doxorubicin (DOX) in the first line treatment of metastatic soft tissue sarcoma (STS) in elderly patients (pts): Results of a phase II study (EPAZ).
2018-05-20

11506 Background: The systemic treatment standard of advanced, inoperable STS in elderly pts is single agent DOX. We tested the hypothesis whether PAZ has comparable efficacy to DOX in elderly STS pts, while offering better tolerability. Methods: Key inclusion criteria: age 360 years, no prior systemic treatment for STS, progressive disease, ECOG 0-2, adequate organ function. DOX 75 mg/m2 q3wks for a total of 6 cycles or PAZ 800 mg OD continuously were given after 1:2 randomization. ECOG 2 and liposarcoma histology were used for stratification. The primary endpoint was progression free survival (PFS) in the per protocol (PP) population. A non-inferiority design was applied with an upper limit of the 95% confidence interval (CI) of less than 1.8. Key secondary endpoints were neutropenia and febrile neutropenia in hierarchical order. EORTC QLQ-C30 was utilized to measure quality of life. Cox regression analysis, ANCOVA and Kaplan-Meier curves were applied (NCT01861951). Results: Between 10/2012 and 03/2016, 39 pts were randomly assigned to DOX and 81 to PAZ. The median follow-up was 11.8 months (mo). The median age was 71 years (range: 60-88). In the PP population, DOX vs. PAZ achieved a PFS of 5.3 vs. 4.4 mo (HR 1.00; 95%CI 0.65-1.53; P = .993), respectively. The incidence of neutropenia CTC grade 4 and neutropenic fever in patients were 56% and 10% for DOX and 0% and 0% for PAZ, respectively. OS was 14.3 vs. 12.3 mo. (HR 1.083; 95%CI 0.68-1.72; P = .735) for the intention to treat population. Most frequent AEs for DOX were fatigue (64.9%), alopecia (56.8%) and nausea (48.6%), and for PAZ fatigue (58.0%), nausea (43.2%) and diarrhea (43.2%). Similar outcome was reported for global EORTC QLQ-C30 measures. Conclusions: This study showed that PAZ was non-inferior compared to DOX, rendering PAZ a putative therapeutic option in the first line treatment of STS of pts above 60 years of age. The distinct AE profile may be used to council pts and tailor therapy to individual needs. Clinical trial information: NCT01861951.Outcome of primary and key secondary endpoints DOX PAZ HR 95%CI P value PFS 5.3 mo 4.4 mo 0.998 0.650-1.533 0.993 Neutropenia grade 4 56% 0% - - < 0.0001 Febrile neutropenia 10% 0% - - 0.003
HepaVac-101 first-in-man therapeutic cancer vaccine phase I/II clinical trial for hepatocellular carcinoma patients.
2018-05-20

TPS3135 Background: HCC is the third leading cause of death from cancer globally with an extremely variable 5-year survival rate. The HepaVac-101 phase I/II, first-in-man, therapeutic cancer vaccine single-arm clinical trial is performed as part of the HepaVac project, funded by the European Commission's 7th Framework Program under the Grant Agreement Nr. 602893 (www.hepavac.eu). The HepaVac-101 trial identification numbers are NCT03203005 (Clinical trials.gov) and 2015-003389-10 (EudraCT). and Methods: The therapeutic cancer vaccine IMA970A is a multi-peptide-based HCC vaccine composed of 16 newly discovered and overexpressed tumor-associated peptides (TUMAPs) directly identified from resected HCC tissues. Of these TUMAPs, 7 are restricted to HLA-A*02, 5 to HLA-A*24 and 4 to HLA class II. CV8102 is a novel RNA based immunostimulatory agent inducing a balanced Th1/Th2 immune response. A total of 40 patients with very early, early and intermediate stage of HCC are enrolled to be treated with a single pre-vaccination infusion of low-dose cyclophosphamide, followed by 9 intradermal vaccinations consisting of IMA970A plus CV8102. The study drugs are applied without concomitant anti-tumor therapy, in order to reduce risk of tumor recurrence/progression in patients having received all indicated standard treatments and without evidence of active disease. The primary endpoints of the HepaVac-101 clinical trial are safety, tolerability, and immunogenicity. Secondary/exploratory endpoints are additional immunological parameters in circulation, infiltrating T-lymphocytes in tumor tissue, biomarkers in blood and tissue, DFS/PFS and OS. Once safety of this vaccination approach has been established in the first 10 patients the addition of a checkpoint inhibitor will be considered. Suitable patients enrolled at Tuebingen are invited to participate in a trial extension investigating an actively personalized vaccine (APVAC). The HepaVac-101 trial is conducted in 6 centers located in 5 European countries. Five centers are actively recruiting patients. As of the time of abstract submission, 4 HCC patients have been screened for HLA haplotype and 1 is eligible for vaccination. Clinical trial information: NCT03203005.
Extended 5-y follow-up (FU) of phase 3 ELOQUENT-2 study of elotuzumab + lenalidomide/dexamethasone (ELd) vs Ld in relapsed/refractory multiple myeloma (RRMM).
2018-05-20

8040 Background: The immunostimulatory monoclonal antibody elotuzumab exhibits a dual mechanism of action, directly activating natural killer cells and mediating myeloma cell death via antibody-dependent cell-mediated cytotoxicity. In ELOQUENT-2 (NCT01239797), ELd showed sustained reduction in risk of disease progression or death at 2- (30%), 3- (27%), and 4-y (29%) FU vs Ld, and a favorable trend in overall survival (final analysis at 427 deaths). Here we present progression-free survival (PFS) data at 5 y, a milestone timepoint in cancer survival analyses. Methods: RRMM patients (pts) randomized 1:1 to ELd or Ld in 28-d cycles until disease progression/unacceptable toxicity. Coprimary endpoints: PFS and overall response rate (ORR) per independent review committee. Results: In all, 646 pts were randomized to ELd (n = 321) and Ld (n = 325). At database lock (Nov 29, 2017), 13% (ELd) vs 7% (Ld) of pts remained on treatment; discontinuation was mostly due to disease progression (55 vs 56%). At 5-y FU (minimum 60 mo), ELd showed 27% reduction in risk of progression or death vs Ld (HR 0.73, 95% CI 0.60–0.87) and relative improvement of 50% in PFS rate at 5 y (18 vs 12%). Pts with ≥very good partial response (ELd 36% vs Ld 30%) had the greatest reduction in risk of progression/death (HR 0.63, 95% CI 0.44–0.89). ORR was 79% (ELd) vs 66% (Ld). G3–4 AEs included blood and lymphatic system disorders (ELd vs Ld: 46 vs 46%), infections (35 vs 27%), vascular diseases (11 vs 8%), second primary malignancies (SPMs; 10 vs 6%), and cardiac disorders (5 vs 8%). Higher rate of any-grade infection (84 vs 75%) and SPMs (17 vs 11%) may reflect longer median duration of treatment with each agent of the ELd vs Ld regimens (E/L/d vs L/d: 17/17/17 vs 12/12 mo). Fewer deaths occurred with ELd than Ld (193 vs 208), mostly due to disease progression. Conclusions: Elotuzumab (+ Ld) has the longest median FU of an immuno-oncology agent in MM. At the milestone timepoint of 5 y, ELd showed sustained, durable clinically relevant improvement in PFS, a 27% reduction in the risk of progression or death, and a safety profile with minimal incremental AEs with ELd vs Ld. Study funding: BMS. Writing support: L Yee, Caudex, funded by BMS. Clinical trial information: NCT01239797.