First-line Chemotherapy In Patients Research Articles

FOLFIRINOX versus Nab-paclitaxel plus gemcitabine in the first-line chemotherapy for patients with advanced pancreatic ductal adenocarcinoma: a multivariate analysis of prognostic factors in a national cohort (Comunica-TTD working group)

FOLFIRINOX versus Nab-paclitaxel plus gemcitabine in the first-line chemotherapy for patients with advanced pancreatic ductal adenocarcinoma: a multivariate analysis of prognostic factors in a national cohort (Comunica-TTD working group)

A phase III study of TAS-118 plus oxaliplatin versus S-1 plus cisplatin as first-line chemotherapy in patients with advanced gastric cancer (SOLAR study)

A phase III study of TAS-118 plus oxaliplatin versus S-1 plus cisplatin as first-line chemotherapy in patients with advanced gastric cancer (SOLAR study)

Prognostic value of tissue plasminogen activator (tPA) in patients with epithelial ovarian cancer undergoing chemotherapy.

Tissue plasminogen activator (tPA) is a key enzyme for fibrin degradation and the proteolytic defense against formation of the thrombotic endothelial deposits. tPA is involved in carcinogenesis but its exact role in tumor biology is not very well understood and a prognostic value of tPA remains ambiguous in different cancers. The aim of the study was to assess the prognostic value of plasma tPA in patients with epithelial ovarian cancer (EOC) in the course of the first line chemotherapy. the study covered 60 patients with EOC who underwent the 1st line chemotherapy. Plasma tPA was assessed at onset, after 3 and 6 cycles of chemotherapy. The groups were stratified according to tPA level at onset of chemotherapy (low tPA group < 6.5 mg/L, N = 37 and high tPA group > 6.5 mg/L, N = 23). Survival analysis was repeated for the cut-off of tPA level at 6.5 mg/L and 5.1 mg/L after 3 and 6 cycles. Only subjects with tPA > 6.5 mg/L at onset of chemotherapy had a significantly lower probability of a 5-year survival (34.8% vs. 72.7%, P < 0.006) and lower chance for disease free survival within 5 years (39.3% vs. 72.7%, P < 0.014). tPA < 6.5 mg/L plasma level evaluated at onset of chemotherapy was an independent marker of better overall survival (RR = 0.44, 95%CI = 0.19-0.98) but not disease-free survival. Plasma tPA may serve as a marker of survival if assessed at onset of the first line chemotherapy in patients with ovarian cancer.

Quality of life outcomes including neuropathy-associated scale from a phase II, multicenter, randomized trial of eribulin plus gemcitabine versus paclitaxel plus gemcitabine as first-line chemotherapy for HER2-negative metastatic breast cancer: Korean Cancer Study Group Trial (KCSG BR13-11)

BackgroundA phase II clinical trial of the comparison between eribulin plus gemcitabine (EG) and paclitaxel plus gemcitabine (PG) as first-line chemotherapy for patients with metastatic breast cancer (MBC) found that the EG regimen was less neurotoxic, but was similar in efficacy to the PG regimen. In the present study, we analyzed functional assessment of cancer therapy-taxane (FACT-Taxane) questionnaires from patients in this clinical trial to determine their quality of life (QoL).MethodsQoL was assessed using the Korean version of the FACT-Taxane questionnaires. After baseline assessment, QoL was assessed every 2 cycles for 12 cycles and every 3 cycles thereafter. The linear mixed model was used to evaluate the difference in QoL between the EG and PG arms.ResultsOf the 118 enrolled patients, 117 responded to the FACT-Taxane questionnaires at baseline, 1 in the PG arm did not. Baseline QoL scores were not different between the EG and PG arms. During treatment, taxane subscale scores were significantly higher in the PG arm than in the EG arm after 2–13 cycles of chemotherapy (all P < 0.05), except for the 11th cycle. Neuropathy-specific analysis showed that patients in the PG arm had earlier and more severe neuropathic symptoms than those in the EG arm (P < 0.001).ConclusionsIn our QoL analysis, the EG regimen delayed and decreased neuropathy as compared with the PG regimen. Therefore, eribulin would be a reasonable substitute for paclitaxel as first-line chemotherapy for MBC.

A retrospective series of centralized reviewed GEP MANECs receiving a first-line adenocarcinoma-oriented chemotherapy.

e15695 Background: Mixed adeno-neuroendocrine carcinomas (MANECs) are very rare malignancies. Due to their biological and clinical heterogeneity, there is not a universally shared clinical approach. Methods: We retrospectively analyzed clinical records of 22 patients from 4 Italian referral centers with advanced MANEC of the gastro-entero-pancreatic (GEP) tract who received a first line chemotherapy and were part of a previously published series of 160 patients (M. Milione et al, Endocrine Related Cancer 2018). Surgical specimens were centrally reviewed by a team of 7 expert pathologists. Clinical and biological data were correlated with outcomes. Results: All patients developed distant metastases (32% synchronous, 68% metachronous). Primary sites were colorectal in 13 patients, esophago-gastro-duodenal in 6, and pancreato-biliary in 3. Ki-67 index in the NEC component was ≥55% in 77% of the patients. Three patients (2 colorectal) received neo-adjuvant chemotherapy, 4 adjuvant (2 colorectal), and 2 peri-operative (one colorectal, one pancreas). The most common regimen was adenocarcinoma-oriented (59% fluoropyrimidines /oxaliplatin). Overall, 14% of patients had a partial response (PR) and 18% stable disease (SD). The median OS in the whole cohort was 0.9 years (95% CI 0.3-1.4). It was longer in patients with Ki-67 &lt; 55% in the NEC component (median 2.5 years; 95% CI 0.5-2.5) than in those with Ki-67 ≥ 55% (median 0.9 years; 95% CI 0.3-1.0) (Wilcoxon P =0.10), regardless of the type of therapy. Mutations in either KRAS (codons 12 and 13) or TP53 (exons 5-8) genes performed by NGS were observed in 9 (8 colorectal, one pancreas) out of 19 patients. Only one of them, (colon primary site), experienced SD. Conclusions: This analysis suggested that an adenocarcinoma-oriented regimen could be active as first line chemotherapy in patients with advanced GEP-MANECs especially with Ki-67 index &lt; 55% in the NEC component. Since its descriptive design and various clinical management, this study cannot either suggest a specific therapy or a real impact of chemotherapy on prognosis. However, it produced solid hypotheses for future prospective-interventional studies in selected populations.

Dendritic-cell vaccine (DCVAC) with first-line chemotherapy in patients with stage IV NSCLC: Final analysis of phase II, open label, randomized, multicenter trial.

9039 Background: Immunotherapy aiming the induction of tumor cell specific immune responses controlling the tumor growth, has emerged as a promising treatment modality in lung cancer(LuCa). Autologous DCVAC can present tumor antigens to elicit a durable immune response. We hypothesized that adding DCVAC to the standard of care chemotherapy (ct) could prolong overall survival (OS) and progression-free survival (PFS). Methods: This study evaluated the efficacy and safety of DCVAC/LuCa (active cellular immunotherapy based on dendritic cells) concomitantly added to ct (carboplatin/paclitaxel) - Arm A (A) vs DCVAC/LuCa + immune modulators (IFN-α and hydroxychloroquine) - Arm B (B)+ct vs ct - Arm C (C) in NSCLC patients (pts). Randomization 1:1:1; pts in A and B received up to 15 doses of DCVAC, ct was given 4-6 cycles in A and C. Stage IV NSCLC was confirmed histologically or cytologically, ECOG 0-1 pts were eligible. Stratification was done by histology subtype and smoking history. Primary efficacy analysis compared A vs C only as enrollment to B was closed early based on Sponsor’s assessment of further clinical development potential, there were no safety concerns or signals. Results: 112 pts at 12 sites were randomized (A/45 B/29 C/38). Patients characteristics were comparable across the study groups with the exception of gender (m/f, %: 65/35 (A) and 74/26 (C) and smoking history (75 % of smokers in A, 97 % in C). Median follow up time was 25.8 months, range 0.1-41.8. Median OS was 15.5 months in A compared to 11.8 months in C, hazard ratio (HR) 0.55, p-value 0.0232, 95% CI [0.33, 0,93], data maturity 77%. Median PFS was 6.74 in A and 5.63 months in C, HR 0.59, p-value 0.0415, 95% CI [0.36, 0.99], data maturity 86%. Overall response rate was 45% in A vs 34% in C. Most TEAEs were related to ct (anemia [35%-A, 32%-C], neutropenia [48% in A, 21%-C], thrombocytopenia [25% in A, 27% in C]). There were no grade ≥ 3 TEAEs solely related to DCVAC. Most common leukapheresis (lp)-related AE was vomiting in 2 pts out of 67 pts undergone lp. Conclusions: Addition of DCVAC-based immunotherapy to the standard of care chemotherapy significantly improved OS in stage IV NSCLC. Clinical trial information: NCT02470468.

Assessment of ramucirumab plus paclitaxel as switch maintenance versus continuation of first-line chemotherapy in patients (pts) with advanced HER2-negative gastric or gastroesophageal junction cancers: The ARMANI phase III trial.

TPS4151 Background: Platinum/fluoropyrimidine regimens are the backbone of first-line therapy for advanced gastric cancer (AGC). The optimal duration of first-line therapy is still unknown and its continuation until disease progression represents the standard. However this strategy is often associated with cumulative toxicity and rapid development of drug resistance. Moreover, only 40% of AGC pts are eligible for second-line treatment. This study aims at assessing whether switch maintenance to ramucirumab plus paclitaxel will extend the progression-free survival (PFS) of subjects with HER-2 negative AGC who have not progressed after a first-line with a platinum/fluoropyrimidine regimen. The hypothesis is that the early administration of an active, non-cross resistant regimen may delay disease progression and, consequently, improve pts’ quality of life. This strategy may also rescue all those subjects that become ineligible for a second-line therapy due to the rapid clinical deterioration. Methods: This is a randomized, open-label, multicenter, phase III trial. Eligibility criteria are: unresectable/metastatic HER-2 negative AGC or gastroesophageal junction (GEJ) cancer; ECOG PS 0-1; measurable and/or evaluable disease by RECIST v1.1; no progression after 3 months of therapy with either FOLFOX4, mFOLFOX6 or XELOX . The primary endpoint is to compare PFS of pts in ARM A (continuation of the same first-line therapy with oxaliplatin/fluoropyrimidine) versus ARM B (switch maintenance to ramucirumab and placlitaxel). Secondary endpoints are: overall survival, time-to-treatment failure, overall response rate, duration of response, percentage of pts receiving a second-line therapy per treatment arm, safety and quality of life. Exploratory analyses to identify primary resistance and prognosis biomarkers are planned, including Next-Generation Sequencing (NGS) on archival tumor tissues. The ARMANI study is sponsored by the Fondazione IRCCS Istituto Nazionale dei Tumori and it is ongoing at 29 Italian centers with a planned population of 280 pts. Clinical trial information: NCT02934464.

Randomized double-blind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients (pts) with metastatic urothelial cancer (mUC): HCRN GU14-182.

4504 Background: Platinum-based chemotherapy for 1st-line treatment of pts with metastatic urothelial cancer (mUC) is typically administered for a fixed duration followed by observation until recurrence. PD-1 blockade with pembro improves survival of pts with mUC progressing despite platinum-based chemotherapy. We explored the potential benefit of earlier use of PD-1 blockade using a "switch maintenance" approach. Methods: Pts with mUC achieving at least stable disease after up to 8 cycles of 1st-line platinum-based chemotherapy were enrolled. Pts were randomized 1:1 to pembro 200 mg IV q3 weeks versus placebo for up to 24 months; pts progressing on placebo could cross over to pembro. Randomization was stratified based on pre-chemotherapy visceral metastases (Y/N) and response to 1st-line chemotherapy (CR/PR vs. SD). The primary objective was to determine the progression-free survival (PFS) as per irRECIST among pts treated with pembro versus placebo. Results: Between 12/2015 and 11/2018, 107 pts were randomized to placebo (n=52) versus pembro (n=55). The baseline pt characteristics are shown in the Table. Pts randomized to placebo and pembro received a median of 6 and 8 cycles, respectively. Excluding patients with baseline CRs, the objective response rate was 12% (5/42) on placebo and 22% (10/46) on pembro. Grade 3-4 treatment emergent adverse events occurred in 48% of pts on placebo and 56% on pembro. At a median follow-up of 14.7 months, 41 pts have died and 26/52 pts randomized to placebo have crossed over to pembro. PFS was significantly longer in patients randomized to pembro vs. placebo (Maximum Efficiency Robust Test p=0.036; log-rank p = 0.038). The 18-month restricted mean progression-free survival time was 5.6 months with placebo and 8.2 months with pembro (p=0.023). Conclusions: Switch maintenance pembro may “deepen” responses achieved with 1st-line chemotherapy. Switch maintenance pembro prolongs PFS in pts with mUC completing 1st-line platinum-based chemotherapy. Clinical trial information: NCT02500121. [Table: see text]

A multicentric phase II randomized trial of docetaxel (D) plus enzalutamide (E) versus docetaxel (D) as first-line chemotherapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): CHEIRON study.

5050 Background: D and E demonstrated to be efficacious in the treatment of mCRPC pts. Due to different antitumor mechanism of action of these agents, it could be postulated that their combination can improve disease control. CHEIRON study tried to demonstrate the candidate efficacy of chemo-hormonal combination D+E versus D in mCRPC first-line. Methods: Eligibility criteria included mCRPC diagnosis, ECOG PS ≤ 2, adequate renal, hepatic and hematological functions, no prior treatment for mCRPC. Pts were randomized to receive D 75 mg/m2 IV d1 q3w plus prednisone 5 mg PO BID for 8 courses alone or plus E 160 mg PO daily for 24 weeks. Stratification criteria were presence of pain and visceral metastases. The primary endpoint of the study was the rate of pts without disease progression (according to PCWG2) at 6 mos after randomization. Results: Between 09/2014 and 10/2017, 246 pts (median age 70 years, range 44-88, pain reported by 54 pts, visceral metastases present in 50 pts) were randomized to DE (120) or D (126). The rate of pts without disease progression at 6 mos was significantly higher in DE arm compared to D arm (89.1% vs 72.8%; p = 0.002). Similarly, a higher proportion of DE pts achieved a PSA reduction ≥ 50% compared to the baseline values compared to the D pts (92% vs 69%; p &lt; 0.0001). No differences were observed in terms of objective response rate. Major haematological toxicities consisted of grade 3-4 neutropenia (13 pts DE – 11 pts D); febrile neutropenia was observed in 10 DE pts and in 6 D pts. At a median follow-up of 24 mos, the median progression free survival was 10.1 mos and 9.1 mos in DE and D arm, respectively (p = 0.01). In DE arm the median overall survival was 33.7 mos compared to 29.6 mos of the standard arm (p NS). Conclusions: The present study was the first phase II randomized trial, which tested the addition of a new generation hormone agent to D compared to D alone. From this data, DE improved the 6-mo disease control with a prolongation of PFS compared to the standard chemotherapy. Clinical trial information: NCT02453009.

Nab-paclitaxel plus gemcitabine versus FOLFIRINOX in the first-line chemotherapy for patients with advanced pancreatic ductal adenocarcinoma: A national cohort (Comunica-TTD working group).

e15707 Background: Advanced pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a five-year overall survival (OS) of less than 5%. Folfirinox and Nab-Paclitaxel plus Gemcitabine (NabPacGem) are the most active treatments in the first-line (1L). The decision to use Folfirinox or NabPacGem is a matter of debate. Methods: A retrospective cohort of advanced PDAC patients treated from January 2011 to May 2018 in four Spanish institutions was analyzed. The principal objective was to compare OS among patients receiving Folfirinox versus NabPacGem in 1L. Progression-free survival (PFS) was a secondary objective. Results: Characteristics of 251 patients included: median age 66.6 years; male 54.4%; stage IV at diagnosis 66.7%; ECOG 0/1/2 18/70/12%; treated with Folfirinox 18.3% and NabPacGem 81.7%. Patients treated with Folfirinox versus NabPacGem were younger (median age 58.3 vs. 67.9; p&lt;0.001) and had lower ECOG (0/1/2 of 46/54/0% vs. 13/71/16%; p&lt;0.001). Univariate analysis: median PFS 5.8 months (95%CI, 4.3 – 7.3) for Folfirinox and 4.2 months (95%CI, 3.7 – 5.2) for NabPacGem, HR=1.53 (95%CI, 1.1 – 2.1; p=0.012); median OS 12.7 months (95%CI, 8.4 – 14.3) for Folfirinox and 7.6 months (95%CI, 5.8 – 8.8) for NabPacGem, HR=1.38 (95%CI, 0.96 – 1.98; p=0.081). Multivariate Cox analysis (including type of treatment, ECOG and age) showed that ECOG was the only variable associated with PFS and OS (Table). Conclusions: In our study, advanced PDAC patients treated with Folfirinox were younger and had a better performance status than those treated with NabPacGem. We found no differences in survival between both treatments when adjusting by ECOG and age.[Table: see text]

Assessment of Ramucirumab plus paclitaxel as switch maintenance versus continuation of first-line chemotherapy in patients with advanced HER-2 negative gastric or gastroesophageal junction cancers: the ARMANI phase III trial

BackgroundPlatinum/fluoropyrimidine regimens are the backbone of first-line chemotherapy for advanced gastric cancer (AGC). However response rates to first line chemotherapy range from 30 to 50% and disease progression occurs after 4–6 cycles. The optimal duration of first-line therapy is still unknown and its continuation until disease progression represents the standard. However this strategy is often associated with cumulative toxicity and rapid development of drug resistance. Moreover, only about 40% of AGC pts. are eligible for second-line treatment.MethodsThis is a randomized, open-label, multicenter phase III trial. It aims at assessing whether switch maintenance to ramucirumab plus paclitaxel will extend the progression-free survival (PFS) of subjects with HER-2 negative AGC who have not progressed after 3 months of a first-line with a platinum/fluoropyrimidine regimen (either FOLFOX4, mFOLFOX6 or XELOX). The primary endpoint is to compare Progression-Free Survival (PFS) of patients in ARM A (switch maintenance to ramucirumab and placlitaxel) versus ARM B (continuation of the same first-line therapy with oxaliplatin/fluoropyrimidine). Secondary endpoints are: overall survival, time-to-treatment failure, overall response rate, duration of response, percentage of patients that will receive a second line therapy according to arm treatment, safety, quality of life. Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues are planned in order to identify potential biomarkers of primary resistance and prognosis.DiscussionThe ARMANI study estimates if patients treated with early swich with ramucirumab plus paclitaxel received benefit when compared to those treated with continuation of first line therapy. The hypothesis is that the early administration of an active, non-cross resistant second-line regimen such as ramucirumab plus paclitaxel may prolong the time in which patients are progression-free, and consequently have a better quality of life. Moreover, this strategy may rescue all those subjects that become ineligible for second-line therapy due to the rapid deterioration of health status after the first disease progression.Trial registrationARMANI is registered at ClinicalTrials.gov (NCT02934464, October 17, 2016) and EudraCT(2016–001783-12, April 202,016).

A multicentric phase II randomized trial of docetaxel (D) plus enzalutamide (E) versus docetaxel (D) as first-line chemotherapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): CHEIRON study.

148 Background: D and E demonstrated to be efficacious in the treatment of mCRPC pts. Due to different antitumor mechanism of action of these agents, it could be postulated that their combination can improve disease control. CHEIRON study tried to demonstrate the candidate efficacy of chemo-hormonal combination D+E versus D in mCRPC first-line. Methods: Eligibility criteria included untreated mCRPC diagnosis, ECOG PS ≤ 2, adequate renal, hepatic and hematological functions. Pts were randomized to receive D 75 mg/m2 IV d1 q3w plus prednisone 5 mg PO BID for 8 courses alone or plus E 160 mg PO daily for 24 weeks. Stratification criteria were presence of pain and visceral metastases. The primary endpoint of the study was the rate of pts without disease progression (according to PCWG2) at 6 mos after randomization. Results: Between 09/2014 and 10/2017, 246 pts (median age 70 years, range 44-88, pain reported by 54 pts, visceral metastases present in 50 pts) were randomized to DE (120) or D (126). The rate of pts without disease progression at 6 mos was significantly higher in DE arm compared to D arm [87.3% (CI95% 64-80) vs 72.6% (CI95% 80-92); p = 0.006). Similarly, a higher proportion of DE pts achieved a PSA reduction ≥ 50% compared to the baseline values compared to the D pts [92.2%(CI95% 61-77) vs 70.0%(CI95% 86-96); p &lt; 0.0001). No differences were observed in terms of objective response rate. Major haematological toxicities consisted of grade 3-4 anemia (3 pts DE – 1 pt D) and grade 3-4 neutropenia (23 pts DE – 19 pts D); febrile neutropenia was observed in 10 DE pts and in 5 D pts. At a median follow-up of 20 mos, the median progression free survival was 11.3 mos (CI95% 10.0-12.7) and 9.1 mos (CI95% 8.9-9.2) in DE and D arm, respectively (p = 0.004). In D arm the median overall survival was 30.5 mos (CI95% 24.1-36.8) compared to 28.7 mos (CI95% 20.7-36.6) of the experimental arm (p NS). Conclusions: From the present study, the first phase II randomized trial testing the addition of a new generation hormone agent to D, DE improved the 6-mo disease control with a prolongation of PFS compared to the standard chemotherapy. Clinical trial information: NCT02453009.

Continuation versus discontinuation of first-line chemotherapy in patients with metastatic squamous cell oesophageal cancer: A randomised phase II trial (E-DIS)

PurposeThe role of chemotherapy has not been established in the treatment of metastatic squamous cell oesophageal cancer (mESCC). Patients and methodsE-DIS is a discontinuation trial, aimed at estimating efficacy, quality of life and safety of chemotherapy continuation (CT-CONT) in patients with mESCC who are free from progression after a selection phase of chemotherapy. The primary end-point was overall survival. ResultsSixty-seven patients were randomised. The 9-month survival rate was 50% (85% confidence interval [CI]: 37–62%) and 48% (85% CI: 35–60%) in the CT-CONT arm and in the chemotherapy discontinuation (CT-DISC) arm, respectively. The time until definitive deterioration of the global health status (European Organisation for Research and Treatment of Cancer [EORTC] core quality of life questionnaire) was 6.6 months (95% CI: 3.3–12.4) for the CT-CONT arm and 4.2 months (95% CI: 2.9–6.3) for the CT-DISC arm, with a hazard ratio (HRCT-DISC/CT-CONT) = 1.44 (95% CI: 0.82–2.53). We observed a beneficial trend in favour of CT-CONT (HR > 1) for most dimensions, including an improvement for three dimensions (dysphagia, eating and oesophageal pain) of the EORTC Oesophageal Cancer Module QLQ-OES18. ConclusionCT-CONT provides an overall survival rate that is similar to CT-DISC. E-DIS trial provides valuable data to support shared decision-making between physicians and patients regarding CT-CONT/DISC.

Abstract P1-14-01: Final results of NorBreast-231, a randomized phase II study evaluating weekly oral vinorelbine versus weekly paclitaxel as first-line chemotherapy in patients with advanced breast cancer

Abstract Background: Single-agent chemotherapy (CT) is the standard treatment option in endocrine receptor (ER)-positive advanced breast cancer (ABC) after failure of endocrine therapy (ET) or in patients (pts) without visceral crisis. Both weekly paclitaxel (WP) and oral vinorelbine (OV) are among the recommended treatment options in this setting. The aim of this study was to evaluate the efficacy and safety profiles of OV and WP in a face to face study. Material and methods: Pts with ER-positive, HER2-negative ABC, with an age ≥18 years and with a documented locally recurrent or metastatic involvement previously untreated by CT were eligible. Pts were randomized to receive, as first-line CT, 3 weekly-cycles of either: ARM A: weekly OV, given as a 80 mg/m2 dose (following a first cycle at 60 mg/m2, dose escalation to 80 in the absence of grade 3 or 4 toxicity at cycle 1); ARM B: WP 80 mg/m2 per week. Primary endpoint was disease control rate (DCR). Pts were stratified according to prior taxane CT and visceral metastases. Results: 131 pts have been treated (OV: 66, WP: 65). Baseline pts characteristics (Arms OV/WP): median age 58/61 years; median number of prior ET: 2/2; prior (neo) adjuvant CT 74/72%; prior anthracycline 67/62%; prior taxane: 41/42%; &amp;gt;3 metastatic sites 42/48%; visceral metastases 79/79%. Median number of cycles (range): 6(1-55)/7(1-44); dose escalation of OV was performed in 75% of pts. Safety: most common non-hematological related G3/4 adverse events per pt were fatigue 8/2%, peripheral neuropathy 0/5%, nausea 3/0%, diarrhoea 3/2%, vomiting 3/0%, constipation 3/2%, alopecia (G2) 2/34%, no toxic deaths; febrile neutropenia was present in 2/0% of pts. Quality of life: over time, no major differences between both arms have been observed. Efficacy: DCR in the intent-to-treat population was [95%CI] 75.8 [63.6-85.5] /75.4 [63.1-85.2]%; overall response rate 20/40%; median progression-free survival: 5.5/6.4 months. Median overall survival was: OV 27.6/WP 22.3 months. Conclusion: Both OV and WP reached similar DCR rates of 75%. Each regimen presented a specific tolerance profile, with, in particular, a lower incidence of alopecia and peripheral neuropathy with OV. OV and WP are valid first-line CT options for ER-positive/HER2-negative pts with ABC. Citation Format: Aapro MS, Hegg R, Ruiz Borrego M, Staroslawska E, Morales S, Cinieri S, De Freitas Junior R, Garcia Estevez L, Szombara E, Hervieu H, Groc M, Villanova GR. Final results of NorBreast-231, a randomized phase II study evaluating weekly oral vinorelbine versus weekly paclitaxel as first-line chemotherapy in patients with advanced breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-14-01.

Abstract P3-11-07: Exploratory biomarker analysis from a phase II, multicenter, randomized trial of eribulin plus gemcitabine(EG) versus paclitaxel plus gemcitabine(PG) as first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)- negative metastatic breast cancer(MBC): Korean cancer study group trial (KCSG BR13-11)

Abstract Introduction : A phase II, multicenter, randomized clinical trial of the comparison between eribulin plus gemcitabine (EG) and paclitaxel plus gemcitabine (PG) as first-line chemotherapy for patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) found EG was less neurotoxic, but had similar efficacy of PG. In this study, we performed exploratory biomarker analysis of the impact of genetic alterations on the efficacy according to EG and PG chemotherapy. Methods : This biomarker study was conducted using tumor samples from 40patients. When tissue collection was possible after disease progression, we performed paired sample analysis. Tumor DNA and RNA were extracted from formalin-fixed, paraffin-embedded tissues. To perform targeted deep sequencing, we used CancerScanTM, a 375 cancer gene panel. And we performed an nCounter expression assay for gene expression analysis using 730 PanCancer panel and 730 Immune panel. Results: In total, we obtained 44 tissue samples from 40 patients. Twenty two patients were assigned in EG arm and 18 patients were in PG arm. Thirty-eight were at baseline and six after disease progression. Gene expression assay were performed in 44 tissue samples but only 31 samples were possible to be targeted deep sequencing. We performed differently expressed gene(DEG) analysis for detecting the association between level of gene expression and disease progression. In this analysis, high expression of CCNE1, TGFB4 and BAMBI and low expression of DDB2, CD14 and SHC3 were associated with disease progression among 730 PanCancer panel genes (p&amp;lt;0.05, respectively). In terms of immune panel genes, most of immune related genes were highly expressed in a group without disease progression compared with that with disease progression. Only 2 genes, C8G and CD24 were highly expressed in a group with disease progression. Paired sample analysis showed that expression levels of THBS4 and CD27 decreased after disease progression while those of CCNE2 and FGFR4 increased. In targeted deep sequencing, FAT3 (42.3%) was most frequently mutated gene followed by PKHD1, PIK3CA and TP53. Among mutated genes, EWSR1 mutation and upstream mutation of ETV1 were associated with disease progression, respectively (p&amp;lt;0.05, respectively). In mutation signature analysis, signature 1 (S, age related), S3(homologous recombination deficiency, HRD), S6 (mismatch repair, MMR), S20(MMR) and S21(microsatellite instability, MSI) were enriched in this population. Mutation signature 3 related to short disease free survival (p=0.0026). Conclusion: In gene expression analysis, high expression of TGF-B signaling pathway related genes was associated with disease progression while high expression of immune related genes were related to prolonged disease free survival. In mutation analysis, EWSR1 and ETV1 mutations indicated short disease free interval and HRD mutation signature was also related to poor prognosis. Citation Format: Kim J-Y, Lee EJ, Park KH, Im S-A, Kim S-B, Sohn SH, Lee KS, Chae YS, Lee KH, Kim JH, Im Y-H, Kim T-Y, Lee K-H, Ahn J-H, Kim GM, Park IH, Lee SJ, Han HS, Kim SH, Jung KH, Park YH. Exploratory biomarker analysis from a phase II, multicenter, randomized trial of eribulin plus gemcitabine(EG) versus paclitaxel plus gemcitabine(PG) as first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)- negative metastatic breast cancer(MBC): Korean cancer study group trial (KCSG BR13-11) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-11-07.

Sorafenib in combination with docetaxel as first-line therapy for HER2-negative metastatic breast cancer: Final results of the randomized, double-blind, placebo-controlled phase II MADONNA study

BackgroundThis multicenter, double-blind phase II study assessed the antitumor activity and toxicity profile of docetaxel with the antiangiogenic multikinase inhibitor sorafenib or matching placebo as a first-line treatment in patients with metastatic or locally advanced HER2-negative breast cancer. Patients and methodsPatients were randomized 1:1 to receive docetaxel 100 mg/m2 on day 1 every 3 weeks in combination with sorafenib 400 mg bid or placebo on days 2–18 of each cycle until tumor progression, or unacceptable toxicity. Sorafenib/placebo could be continued at the investigator's discretion if docetaxel was stopped due to toxicity. Primary endpoint was progression free survival (PFS). ResultsFrom October 2008 to December 2013, 102 patients were randomized; 98 patients were evaluable. The trial was prematurely terminated due to slow accrual. Due to increased toxicity the dose of docetaxel was reduced to 75 mg/m2 and an increasing sorafenib dosing schedule was implemented as part of a protocol amendment. The addition of sorafenib to docetaxel did not improve PFS (8.2 vs. 7.3 months for docetaxel/placebo; HR 0.84, log rank p = 0.43), but led to higher rates of early treatment discontinuation. There were no statistically significant differences between sorafenib dosing schedules. ConclusionsAddition of sorafenib to taxane-based first-line chemotherapy in patients with metastatic breast cancer failed to improve PFS and resulted in increased toxicity.

Evaluation of safety and tolerability of durvalumab (D) and tremelimumab (T) in combination with first-line chemotherapy in patients (pts) with esophageal squamous-cell carcinoma (ESCC).

146 Background: Platinum-doublet chemotherapy in first-line (1L) ESCC pts has reached a therapeutic plateau, and new therapeutic strategies are needed. Adding D (anti-PD-L1 mAb) and T (anti-CTLA-4 mAb) to 1L platinum-based chemotherapy may improve outcome in pts with advanced/metastatic ESCC. Methods: In Part A of this Phase 1b study (NCT02658214), dose-limiting toxicities (DLTs) for D+T (D 1.5 g + T 75 mg on d1, q4w) plus 5-FU+cisplatin (5-FU 800 mg/m2 + cisplatin 80 mg/m2 d1-5, q4w) were evaluated for the first 4 cycles in pts with advanced/metastatic ESCC who were eligible for 1L chemotherapy. The primary objective was safety and tolerability and exploratory objectives included antitumor activity and biomarker analysis. Results: Pts (N = 6) were enrolled to receive D+T + 5-FU+cisplatin between November 13, 2017, and February 14, 2018. Median age was 56 years, 83% were male, and all were ECOG PS 1. Four pts had recurrent disease and 2 were newly diagnosed with advanced/metastatic disease. All 6 pts had ≥1 treatment-related adverse event (trAE), 3 pts had grade ≥3 trAEs. All pts experienced 5-FU+cisplatin-related AEs. All grade ≥3 trAEs were neutropenia and considered due to 5-FU+cisplatin treatment; 2 were grade 3 and 1 was grade 4, which was the only serious trAE reported. Two pts had D- and/or T-related trAEs. Immune-mediated AEs were grade 1 or 2 and included diarrhea (n = 1), pruritus (n = 1), rash (n = 1), and increased AST (n = 1). There were no trAEs that led to discontinuation or death. Two of the 6 pts had a confirmed partial response that was ongoing at data cutoff (June 29, 2018). Conclusions: For patients in the ESCC DLT evaluation cohort, D+T + 5-FU+cisplatin was tolerable, and no unexpected toxicities occurred. No DLTs were observed for this regimen. The majority of trAEs and all trAEs grade ≥3 were attributed to 5-FU+cisplatin, and all were manageable. AEs related to D and/or T were all grade 1 or 2. No treatment discontinuation or death was attributed to trAEs. The study has been expanded to further evaluate this regimen in additional patients for efficacy, safety, and biomarkers. Clinical trial information: NCT02658214.

Low burden of minimal residual disease prior to transplantation in children with very high risk acute lymphoblastic leukaemia: The NOPHO ALL2008 experience.

The population-based Nordic/Baltic acute lymphoblastic leukaemia (ALL) Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol combined minimal residual disease (MRD)-driven treatment stratification with very intense first line chemotherapy for patients with high risk ALL. Patients with MRD ≥5% at end of induction or ≥10-3 at end of consolidation or following two high risk blocks were eligible for haematopoietic cell transplantation (HCT) in first remission. After at least three high risk blocks a total of 71 children received HCT, of which 46 had MRD ≥5% at end of induction. Ten patients stratified to HCT were not transplanted; 12 received HCT without protocol indication. Among 69 patients with evaluable pre-HCT MRD results, 22 were MRD-positive, one with MRD ≥10-3 . After a median follow-up of 5·5years, the cumulative incidence of relapse was 23·5% (95% confidence interval [CI]: 10·5-47·7) for MRD-positive versus 5·1% (95% CI: 1·3-19·2), P=0·02) for MRD-negative patients. MRD was the only variable significantly associated with relapse (hazard ratio 9·1, 95% CI: 1·6-51·0, P=0·012). Non-relapse mortality did not differ between the two groups, resulting in disease-free survival of 85·6% (95% CI: 75·4-97·2) and 67·4% (95% CI: 50·2-90·5), respectively. In conclusion, NOPHO block treatment efficiently reduced residual leukaemia which, combined with modern transplant procedures, provided high survival rates, also among pre-HCT MRD-positive patients.

Impact of primary tumor location in patients with RAS wild-type metastatic colon cancer treated with first-line chemotherapy plus anti-EGFR or anti-VEGF monoclonal antibodies: a retrospective multicenter study.

Emerging evidence supports a prognostic role of primary tumor location in metastatic colon cancer (mCC). We conducted a retrospective analysis to evaluate the effect of tumor location on prognosis and efficacy of biological agents (anti-EGFR, Cetuximab and Panitumumab, or anti-VEGF, Bevacizumab) added to first-line chemotherapy in patients with RAS wild-type (wt) mCC. Patients with newly diagnosed RAS wt mCC candidates to first-line chemotherapy with anti-EGFRs or Bevacizumab were selected. Clinical outcomes were assessed and stratified by tumor location and type of treatment. Overall, 351 patients met the inclusion criteria. Primary colon cancer was right-sided (RCC) in 105 (29.9%) patients and left-sided (LCC) in 246 (70.1%). Patients with LCC had a better OS compared to those with RCC (33.6 vs 23.5 months, HR 0.74; 95% CI, 0.55 to 0.99; p=0.049). In the overall study population, OS was not significantly different for patients treated with Cetuximab or Panitumumab as compared to those receiving Bevacizumab. However, when comparing treatment outcome according to tumor sidedness, patients with LCC treated with Cetuximab or Panitumumab had a significantly longer PFS (12.4 vs 10.7 months; HR: 0.69; 95% CI, 0.51 to 0.93; p= 0.015) and OS (40.7 vs 28.6 months; HR: 0.67; 95% CI 0.47 to 0.95; p= 0.026). No relevant differences were observed in patients with RCC.We found evidence in support of the impact of tumor location in RAS wt mCC treated with first-line chemotherapy in association with targeted therapy. More favorable outcomes were observed in LCC patients, but not in RCC patients, treated with anti-EGFR agents compared with those who received Bevacizumab. Further, prospective and adequately sized studies are warranted to confirm our findings.

Impact of the occurrence of new lesions on the survival of patients who undergo chemotherapy for metastatic colorectal cancer.

In clinical practice, the efficacy of chemotherapy for metastatic colorectal cancer (mCRC) is typically evaluated according to the Response Evaluation Criteria in Solid Tumours (RECIST) criteria, and an appropriate treatment plan is determined. In the case of progressive disease (PD), the components of the treatment are altered; however, PD, as defined by the RECIST criteria, includes various types of progression. While detailed consideration regarding the impact of the growth pattern of measurable target lesions on survival has been performed, the impact of the occurrence of new lesions on survival is unclear. The aim of the present study was to assess the impact of the occurrence of new lesions on the survival of patients who underwent chemotherapy for mCRC. Among the patients who received doublet chemotherapy for mCRC as a first-line treatment between 2008 and 2016, 81, who stopped the chemotherapy due to PD, were enrolled in the present study. The types of progression were classified according to the definitions of RECIST. Subsequently, the following criteria were considered: The growth of measurable target lesions, the occurrence of new lesions and the unequivocal progression of non-target disease. Furthermore, the developing patterns of new lesions were also assessed. The association between the type of progression and the survival after the failure of the first-line chemotherapy was explored. Forty (49.4%) patients only experienced growth of measurable target lesions, 41 (50.6%) of the patients had new lesions and 3 (3.7%) of the patients had unequivocal progression of non-target disease. The survival rate from the discontinuation of first-line chemotherapy in patients with new lesions was significantly worse than that in patients without new lesions (P=0.0068); however, the developing patterns of new lesions were not associated with survival. Regardless of the developing patterns of new lesions, patients who stopped chemotherapy due to new lesions had worse survival rates from the discontinuation of first-line chemotherapy compared with those who stopped chemotherapy due only to the growth of measurable target lesions. Because the occurrence of new lesions represents severe progressive disease, patients with new lesions may require more intensive chemotherapy. The type of progression may be useful information for selecting the appropriate treatment following the failure of first-line chemotherapy.