julilili42/papers huggingface dataset:
Impact of 12 weeks nab-paclitaxel + carboplatin or gemcitabine followed by anthracycline administration according to pCR in triple-negative early breast cancer: Survival results of WSG-ADAPT-TN phase II trial.
2018-05-20

573 Background: Optimal chemotherapy in TNBC EBC is unclear. ADAPT TN demonstrated higher pCR (46% vs. 29%) and better safety for only 12 weeks nab-paclitaxel/carboplatin vs nab-paclitaxel/gemcitabine (JNCI 2017). Methods: Patients with centrally confirmed TNBC (ER/PR < 1%, HER2-, cT1c-cT4c, cN0/+) were randomized to neoadjuvant A: 4x nab-paclitaxel 125 mg/m2/gemcitabine 1000 mg/m2 d1,8 q3w vs. B: 4x nab-paclitaxel 125 mg/m2/carboplatin AUC2 day 1/8 3-weekly (q3w). Primary endpoint was pCR (ypT0/is/ypN0) after 12 weeks of therapy. Event-free (EFS) -- defined as time from registration to any invasive relapse, secondary malignancy or death of any cause -- and overall survival (OS) were secondary endpoints. Adjuvant anthracycline-based chemotherapy (4xEC) was optional in patients with pCR. Here, we report the per-protocol interim survival analysis recommended by the DSMB after a median follow-up of 3 years. Results: 336 patients were enrolled (48 centers, arms A/B: n = 182/154). Median age was 50 years. At baseline, about 63% had cT2-4c tumors, 26.2% were clinically node-positive. After 36 months median FU, 68 EFS events (A/B: 37/29) and 37 deaths (A/B: 24/13) were observed. pCR (vs. non-pCR) is highly prognostic for EFS (3y EFS: 92% vs. 71%, p < 0.001) and OS (3y OS: 99.1% vs. 81.6%, p < 0.001). Despite the strong impact of carboplatin on pCR, 3y EFS was similar in (77.6% vs. 80.8%) in both arms; OS was numerically higher in Arm B (84.7% vs. 92.2%, p = 0.09). Final analysis regarding anthracycline use and its survival impact will be presented at the meeting. Conclusions: 12w nab-paclitaxel/carboplatin is a tolerable and effective neoadjuvant option in early stage TNBC. In ADAPT TN, the strong impact of carboplatin vs. gemcitabine on pCR seems to be "mitigated" regarding survival by subsequent adjuvant anthracycline/cyclophosphamide therapy. Our findings provide first prospective evidence supporting individualized chemotherapy regimens in early TNBC. Clinical trial information: NCT01815242.
Randomized phase II trial of trofosfamide vs. adriamycin in elderly patients with previously untreated metastatic soft tissue sarcoma.
2018-05-20

11507 Background: DOX is still the standard in metastatic STS. We assessed the efficacy and safety of oral TRO. Methods: This is a randomized phase 2 trial at 15 german and 1 french centers. We included pts with metastatic high-grade STS, older than 60 yrs of age, with an ECOG of 0-1. They were randomly (1:2) assigned to either (A) DOX (60 or 75 mg/sqm i.v., on day 1, q 22 d for 6 cycles) or arm B (oral TRO, 300 mg, d1-7, then 150mg daily continuously p.o.) as first-line tx. Randomisation was stratified by presence of liver mets, and PS (0 vs 1). Pts were treated until PD or unacceptable toxicity. Primary aim was a 6-months (mos) PFS rate of at least 20 % in Arm B; secondary: safety, ORR, survival. Results: Between 8/04 and 10/12 40 pts were randomly assigned to arm A and 80 to Arm B, median age 70 yrs (60-89). Median duration of f/u of surviving patients was 18.4 mos (range, 3.8-94.7). Median treatment duration was 2.8 mos (0-4.6) in A and 2.8 mos (0.4-41.4) in B. No difference in terms of ORR with 7.7% (1.6-20.9) in arm A and 6.7% (2.2-14.9%) in arm B (p = 0.99); disease control rate (including disease stabilization) (53.8% (95%-CI, 37.2-69.9%) vs. 41.3% (95%-CI, 30.1-53.3%), p = 0.23), PFS (4.3 mos; 95%-CI, 2.2-5.9 vs. 2.8 mos; 95%-CI, 1.6-3.5), p = 0.99) and OS (9.6 mos; 95%-CI, 6.4-11.6 vs. 12.1mos; 95%-CI, 9.5-16.0), p = 0.59) were seen, without difference in ITT- and per-protocol populations. Duration of response lasted 5.0 mos in arm A (range, 1.3-8.0) and 4.0 mos (0-46.6) in arm B; however, in pts achieving a CR or PR duration was longer in favor of cohort B (0 vs. 27.7 mos resp. 4.3 vs. 8.2 mos). Primary study endpoint (6-mos PFR) was 27.6% in Arm B (95%-CI, 18.0-39.1). Safety analyses in 115 pts showed at least one side effect in 97.4% vs. 96.1% pts (p = 0.99); of note, side effects G3-4 were lower in favor of Arm B (59% vs. 30.3%; p = 0.005). TRO caused more often dyspnoe, fatigue (but only minor degree); DOX leukocyto- and neutropenia as well as mucositis, G1-4. Discontinuation rate other than PD was 15.4% vs. 7.9%. Conclusions: In an elderly population of pts who received either standard Dox or oral TRO for metastatic STS, equal median PFS and OS have been achieved. TRO associated with a more favorable toxicity profile. Clinical trial information: 00204568.
Olaparib in German routine clinical practice: Updated interim results of the non-interventional study C-PATROL.
2018-05-20

e17549 Background: The PARP inhibitor olaparib is approved in the EU for maintenance therapy of BRCA-mutated (BRCAm+) platinum-sensitive relapsed ovarian cancer patients, who are in response to their most recent platinum-based chemotherapy. So far, only limited data on real-world olaparib treatment are available. Methods: The German prospective, non-interventional study C-PATROL (NCT02503436) collects real-world clinical and patient-reported outcome data in patients with BRCAm+ platinum-sensitive relapsed ovarian cancer treated with olaparib capsules according to EU label. Interim analyses generate data on patient characteristics, safety and dosing, thereby providing real word data on olaparib monotherapy as maintenance treatment within the first years after the German market access in JUN2015. Data are analyzed by descriptive statistics. Results: 75 patients with ≥3 mths of observation after start of olaparib therapy were analyzed in 1st interim analysis (cut-off: 06APR2017; median age: 61 [45 to 80] yrs; ECOG ≤ 1: 93.3%; ≥2 relapses: 49.3%; ≥ 3 prior platinum-based chemotherapeutic regimens: 46.7%). Data were stratified according to subgroups (age: < 70 [57 pts] vs. ≥70 yrs [18 pts]; comorbidities: yes [35 pts] vs. no [36 pts] vs. unknown [4 pts]). Patients started with a median daily dose of 800 [300 to 800] mg olaparib. 29.3% of patients had at least one dose reduction and at least one dose interruption (with a median duration of 10 [2 to 51] days). Olaparib was permanently stopped for 36% of patients mainly due to progression (81.5%), and for 3 patients (11%) due to an adverse event. 85.3% of patients had any adverse event. Anemia (34.7%), nausea (29.3%) and fatigue (26.7%) occurred most frequently, with anemia and nausea being more frequent in patients < 70 years and without comorbidities. Results will be updated according to the 2nd interim analysis (cut-off: 01FEB2018) including at least 150 patients. Conclusions: Current data from the ongoing non-interventional study C-PATROL indicate that olaparib is well tolerated under routine conditions. Adverse events are generally manageable and the toxicity profile is in line with results of the clinical trial program of olaparib. Funding: AstraZeneca Clinical trial information: NCT02503436.
Adverse events of special interest in the phase 3 COLUMBUS study.
2018-05-20

9567 Background: Combination BRAF/MEK inhibitor (BRAFi/MEKi) therapy is standard of care for BRAFV600-mutant metastatic melanoma. In COLUMBUS Part 1, encorafenib 450 mg once daily (QD) + binimetinib (BINI) 45 mg twice daily (BID) (COMBO450) reduced risk of progression or death vs encorafenib 300 mg QD (ENCO300) or vemurafenib 960 mg BID (VEM) in patients (pts) with advanced BRAFV600-mutant melanoma. Adverse events of special interest (AESIs) including pyrexia, serous retinopathy, photosensitivity, and rash are reported here. Methods: Pts were randomized 1:1:1 to receive COMBO450, ENCO300, or VEM. Pts had standard physical and laboratory assessments, and regular dermatologic, cardiac, and ophthalmologic evaluations. AESIs comprised known effects of available BRAFi and/or MEKi. Results: Safety was evaluated in 192, 192, and 186 pts in the COMBO450, ENCO300 and VEM arms, respectively. Median duration of exposure to treatment was 51 weeks for each component in the COMBO450 arm, 31 weeks in the ENCO300 arm, and 27 weeks in the VEM arm. Pyrexia incidence with COMBO450 was low (grade 1/2: 14%; grade 3: 4%) and led to treatment discontinuation in 1% of pts and to dose modification in 4%. Photosensitivity was infrequent with COMBO450 (grade 1/2: 4%; grade 3: 1%), required dose modification in 1% of cases, and did not lead to treatment discontinuation. Rash occurred in 22% of pts with COMBO450 (grade 1/2: 21%, grade 3: 1%, grade 4: 1%), led to discontinuation in 0.5%, and to dose modification in 2%. Serous retinopathy (grade 1/2: 17%; grade 3: 3%) and left ventricular dysfunction (grade 1/2: 6%; grade 3: 2%) with COMBO450 did not lead to discontinuation and were generally reversible (in 89% and 93% of pts, respectively). Conclusions: Common BRAFi/MEKi toxicities were generally manageable and reversible and were infrequently associated with treatment discontinuation. Pyrexia and photosensitivity were uncommon with COMBO450. The observed safety profile suggests COMBO450 may provide a meaningfully differentiated treatment option for patients with BRAFV600-mutant melanoma. SPONSOR: Array BioPharma Inc. Clinical trial information: NCT01909453.
Next-generation-sequencing of advanced melanoma: Which genetic alterations have an impact on systemic therapy response?
2018-05-20

e21557 Background: Next-generation sequencing will gain more and more importance for melanoma patients. Detection of genetic alterations in tumor tissue may help to understand mechanisms of resistance to immunotherapy or targeted therapy. Taking those resistance mechanisms into account from the outset of disease, it would be easier to choose the “individual” best treatment option, especially in patients with an existing BRAFV600 mutation. Methods: Since March 2017, we have routinely performed NGS diagnostics (including ≥ 336 genes) in tumors of advanced melanoma patients with limited treatment options. The first 50 deeply (300-500x) sequenced tumor samples of 50 different patients have now been evaluated. We matched the sequencing results with clinical data to determine whether there are any risk factors associated with treatment failure, such as combined treatment with ipilimumab and nivolumab. Results: 29 men and 22 women were included, median age was 61 years (IQR 49-75). The different melanoma types were: mucosal melanoma (MM) (n = 7), acral lentiginous melanoma (ALM) (n = 6), uveal melanoma (UM) (n = 6), other melanoma of the skin (n = 32). 21/32 (66%) of the patients had progressive disease under combined therapy with ipilimumab and nivolumab for metastases. Median mutational load was 5.6 variants / Mbp. The lowest mutational load was found in the subgroups of MM, ALM and UM. Interestingly we found more frequently copy number variants (CNVs) and single nucleotide variants (SNVs) in these subgroups. We outline the most frequent CNVs and SNVs and work out in particular what changes have been found in the area of cell cycle regulation and DNA damage response. In this setting we show that certain deletions and/or amplifications are more common in immunotherapy-resistant patients. Conclusions: Our analysis demonstrates the importance of NGS in advanced melanoma patients. The results may help to understand resistance mechanisms and therefore to find the best treatment option to start. Furthermore, new therapeutic options such as targeted drugs might be available for patients suffering resistance to established treatments. In this context, molecular tumor boards have a great importance.
Access to innovative medicines for metastatic melanoma worldwide: Melanoma World Society and European Association of Dermato-oncology survey in 34 countries.
2018-05-20

According to data from recent studies from Europe, a large percentage of patients have restricted access to innovative medicines for metastatic melanoma. Melanoma World Society and European Association of Dermato-oncology conducted a Web-based survey on access to first-line recommended treatments for metastatic melanoma by current guidelines (National Comprehensive Center Network, European Society for Medical Oncology [ESMO] and European Organization for Research and Treatment of Cancer/European Association of Dermato-oncology/European dermatology Forum) among melanoma experts from 27 European countries, USA, China, Australia, Argentina, Brazil, Chile and Mexico from September 1st, 2017 to July 1st, 2018. Data on licencing and reimbursement of medicines and the number of patient treated were correlated with the data on health expenditure per capita (HEPC), Mackenbach score of health policy performance, health technology assessment (HTA), ASCO and ESMO Magnitude of clinical benefit scale (ESMO MCBS) scores of clinical benefit and market price of medicines. Regression analysis for evaluation of correlation between the parameters was carried out using SPSS software. The estimated number of patients without access in surveyed countries was 13768. The recommended BRAFi + MEKi combination and anti-PD1 immunotherapy were fully reimbursed/covered in 19 of 34 (55.8%) and 17 of 34 (50%) countries, and combination anti-CTLA4+anti-PD1 in was fully covered in 6 of 34 (17.6%) countries. Median delay in reimbursement was 991 days, and it was in significant correlation with ESMO MCBS (p = 0.02), median market price (p = 0.001), HEPC and Mackenbach scores (p < 0.01). Price negotiations or managed entry agreements (MEAs) with national authorities were necessary for reimbursement. In conclusion, great discrepancy exists in metastatic melanoma treatment globally. Access to innovative medicines is in correlation with economic parameters as well as with healthcare system performance parameters. Patient-oriented drug development, market access and reimbursement pathways must be urgently found.
FOLFIRI plus ramucirumab versus paclitaxel plus ramucirumab for patients with advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction as second-line therapy: The RAMIRIS study.
2018-05-20

TPS4132 Background: The majority of patients with gastroesophageal cancer present with inoperable or metastatic disease. After failure of first-line chemotherapy, ramucirumab is a proven option as monotherapy and in combination with paclitaxel as second line treatment in advanced gastric cancer. Irinotecan has shown significant improvement of overall survival compared to best supportive care (BSC) in the second line setting and is an accepted safe and efficient standard chemotherapeutic treatment for patients with refractory gastroesophageal cancer. More and more patients get treated with taxanes in the perioperative or 1st line metastatic setting. For those patients the benefit of a combination of ramucirumab and paclitaxel is unclear, and many physicians would choose an irinotecan based regimen as second line treatment. This provides a rationale for the evaluation of FOLFIRI + ramucirumab. Methods: This is a prospective, multicenter, randomized, investigator initiated phase II trial. Patients with advanced gastric or esophagogastric junction cancer will be randomized 2:1 to FOLFIRI (irinotecan 180 mg/m2; 5-FU 400 mg/m2; leucovorin 400 mg/m2; 5-FU 2400 mg/m2 on day 1 and 15 of a 28-day cycle) plus ramucirumab 8mg/kg every two weeks (Arm A) or paclitaxel 80 mg/m2 (days 1, 8, 15 of a 28-day cycle) plus ramucirumab 8mg/kg every two weeks (Arm B). Primary endpoint of the trial is OS rate after 6 months, based on the ITT population. The experimental therapy (FOLFIRI + Ramucirumab; n = 67) is considered to be a highly promising candidate for further development (e.g. in a phase III trial), if the true OS rate amounts to 65% or more, as this corresponds to the efficacy of the standard ramucirumab-paclitaxel regimen according to the RAINBOW study in the western population. Secondary endpoints are progression-free survival, response rate, safety and tolerability. Currently (Jan 2017) 40 of planned 111 patients are randomized. Clinical trial information: NCT03081143.
Impact of tumor-infiltrating lymphocytes on response to neoadjuvant chemotherapy in triple-negative early breast cancer: Translational subproject of the WSG-ADAPT TN trial.
2018-05-20

12102 Background: In triple-negative breast cancer (TNBC), pathological complete response (pCR, ypT0/is/ypN0) is associated with improved prognosis. The randomized prospective WSG-ADAPT TN phase II trial showed higher pCR with Nab-paclitaxel / Carboplatin (NP/C) compared to paclitaxel / gemcitabine (NP/G) as 12-week neoadjuvant therapy. Presence of tumor-infiltrating lymphocytes (TILs) is associated with increased pCR rates after neoadjuvant chemotherapy, but the role of TIL dynamics during (specific) chemotherapy regimens is still unknown. Methods: This pre-planned translational analysis focuses on semi-quantitative TIL measurements in ADAPT-TN among tumor samples at baseline (TIL-0) and after 3 weeks of chemotherapy (TIL-3). Associations of continuous TIL-0 and TIL-3 levels with pCR, with chemotherapy arm and with other clinical / pathological measurements were analyzed using logistic regression, rank correlations, t and chi-square statistics. Results: 336 patients were enrolled. TIL-0 and TIL-3 were available among 311 (92.6%) and 223 (66.4%) patients, respectively. "Low cellularity" in 3-week biopsies (tumor necrosis, lack of invasive tumor cells) was recorded in 82 patients. TIL-0 and TIL-3 were strongly correlated (0.64, p < .001); average relative increase was about 30%. TIL-0 was significantly associated with baseline tumor grade, clinical tumor size, and nodal status. TIL-3 was significantly associated with nodal status and grade in both biopsies. In all patients, higher levels of both TIL-0 (p < .001) and TIL-3 (p = .002) were associated with pCR. Higher TIL-0 was also significantly associated with pCR in both arms separately. "Low cellularity" was also associated with pCR in all patients (OR = 3.9, 95%-CI: 2.3-6.8) and in both arms separately (NP/G: OR = 3.6, 95%-CI: 1.7 to 7.9; NP/C: OR = 4.2, 95%-CI: 1.9-9.3). Conclusions: In TNBC patients, higher levels of tumor-infiltrating lymphocytes were associated with pCR, both at baseline and after 3 weeks of neoadjuvant chemotherapy. "Low-cellularity" at week 3, which indicates extensive response to chemotherapy, was itself strongly associated with response to therapy.
Effectiveness and safety of pazopanib (PAZO) and everolimus (EVE) in a changing treatment (Tx) landscape: Interim results of the non-interventional study PAZOREAL.
2018-05-20

4584 Background: The therapeutic landscape for metastatic renal cell carcinoma (mRCC) has evolved rapidly with the approval of targeted therapies like tyrosine kinase-, mTOR-, multikinase-, and immune checkpoint inhibitors. Real-world data are urgently needed to monitor the translation of these approaches into daily practice. Methods: PAZOREAL is a prospective, non-interventional study to evaluate efficacy, tolerability, safety, and quality-of-life (QoL) in mRCC patients (pts) treated with first-line PAZO, second-line nivolumab (NIVO) or EVE, or third-line EVE (± lenvatinib) after NIVO. The primary variable was time on drug (TD) in the respective Tx lines. Other endpoints were overall survival (OS), dosing, safety, and QoL. Results: Between Dec 2015 and Nov 2017, 421 pts were enrolled. Interim results for 385 pts treated with PAZO in first line are presented here, majority of pts presented with ECOG 0-1 (81.0%) and clear cell carcinoma (80.3%). Median TD was 6.5 months (95%CI, 5.5-8.3). Using commonly applied trial eligibility criteria i.e. Karnofsky PS ≥ 70%, normal hemoglobin and clear-cell histology, the median TD in trial-eligible pts (39.5% of 385 pts) was 8.0 months (95%CI, 6.2-11.2). Progressive disease (n = 104/212 pts) was the most common reason for end of PAZO Tx, followed by toxicity (n = 34) and unrelated adverse events (AEs) (n = 20). 75 pts subsequently received NIVO as second-line treatment. Median OS was not reached. Death was reported for 20.8% of pts. Survival follow-up is ongoing. PAZO Tx was well tolerated. Treatment-emergent AEs (TEAEs) were reported for 308 of 378 pts included in the safety analysis, PAZO-related TEAEs for 246 pts (65.1%), and PAZO-related grade 3/4 TEAEs for 75 pts (19.8%). Most commonly reported AEs were diarrhea, nausea, and fatigue. QoL evaluated by EQ-5D-5L remained stable during PAZO Tx. Conclusions: The PAZOREAL study demonstrated acceptable efficacy, safety and tolerability of PAZO in the real-world setting. For patients considered trial-eligible, TD was comparable with results from clinical trials. The sequence of PAZO followed by NIVO as second line Tx is commonly applied in Germany.
RIBECCA: A phase IIIb, multi-center, open label study for women with estrogen receptor positive locally advanced or metastatic breast cancer treated with ribociclib (LEE011) in combination with letrozole—Results of the first interim analysis.
2018-05-20

1051 Background: RIBECCA is a national, multi-center, open-label, single-arm phase IIIb trial assessing the efficacy and safety of ribociclib in combination with letrozole in a patient population similar to the populations of MONALEESA-2, -3 and -7. Here we present the results of the first preplanned interim analysis. Methods: Main inclusion criteria allow enrollment of men or women with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy, and histological or cytological confirmation of ER+, HER2- breast cancer, irrespective of their menopausal status. The primary objective is to assess the clinical benefit rate (CBR) after 6 months, secondary objectives include progression free survival (PFS), overall survival (OS), safety and changes in quality of life. Results: The cut-off date for this first interim analysis was 12 months after the enrollment of the first patient (24-Oct-2017). Here we describe the baseline characteristics and safety data of patients (pts) with at least 12 weeks follow up (n = 338). Baseline characteristics: of 338 pts, 336 were female and 2 male. Median age: 64 yrs; 46 pts pre-or perimenopausal, 290 postmenopausal; ECOC 0-1: 97.3%; median time since first recurrence: 2 months; 74.3% pts had bone metastases, 31.4% liver, 26.9% lung and 28.4% other metastases. 79.6% of pts had received at least one prior endocrine therapy or chemotherapy: 39.5% in the (neo-) adjuvant setting, 39.9% in the palliative setting. Median relative dose intensity was 0.944 for ribociclib and 1 for letrozole. The most common treatment emergent AEs (all grades) were neutropenia (42.3%), nausea (36.7%), fatigue (33.4%), alopecia (29%), diarrhea (20.7%), leukopenia (19.5%), constipation (17.8%), ALT increased (17.1%), AST increased (15.7%) headache (15.9%) and neutrophil count decreased (12.7%). Conclusions: The results of the first interim analysis in this additional patient population are in line with data published from the pivotal phase III studies MONALEESA-2 and MONALEESA-7. No new safety signals were detected. Clinical trial information: NCT03096847.