First-line Chemotherapy In Patients Research Articles

Switch Maintenance Gemcitabine after First Line Chemotherapy in Patients with Malignant Mesothelioma: A Randomized Open Label Phase II Trial (NVALT19)

Background: All patients with malignant mesothelioma develop progressive disease after first line therapy. Some studies have addressed maintenance therapy, none showed a great impact. Gemcitabine, an active drug in mesothelioma, was tested in the NVALT19 study in a switch maintenance setting. Methods: This open label randomized phase II study in 18 Dutch hospitals, recruited patients with unresectable mesothelioma who did not progress after first line chemotherapy (platinum-pemetrexed), World Health Organization performance status ≤ 2 and an adequate organ function. Key exclusion criteria were seriously disabling conditions or symptomatic central nervous system metastases. Patient were 1:1 randomised to maintenance gemcitabine (1250 mg/m2, intravenous, day 1 and 8, 3 weeks schema) or best supportive care (BSC,) using minimisation method. Primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Safety was analysed in all participants who received one dose of study drug. Findings: From March 20, 2014, to February 27, 2019, 130 patient were randomized (65 to gemcitabine and 65 to BSC). PFS was significant longer with gemcitabine (median 6.2) than with BSC (3·2 months; hazard ratio (HR) 0·46; 95% confidence interval [CI], 0·31 to 0·68; p<0·001). The benefit was confirmed by independent central review (HR 0·47; 95% CI, 0·32 to 0·69; p<0·001). Grade 3- 4 adverse events occurred in 33 (51%) patients in the gemcitabine arm and in 10 (16%) patients in the BSC arm. One patient died likely due to a gemcitabine related infection. Interpretation: Switch maintenance gemcitabine, after first line chemotherapy, significantly prolonged progression free survival compared to BSC alone among patients with malignant mesothelioma. The study confirmed the activity of gemcitabine in malignant mesothelioma. Trial Registration: This study is registered in the Netherlands Trial registry; NTR4132/NL3847. Funding Statement: Dutch Cancer Society (KWF Kankerbestrijding) and the NVALT Study Group. Declaration of Interests: PB participated in advisory boards of Merck Sharp & Dohme and Bristol-Myers Squibb. RC participated in advisory boards of Merck Sharp & Dohme and Roche, and received speakers fee from Roche, Pfizer and BristolMyers Squibb. HJMG has received research funding from Lilly, Novartis, Roche-Genentech, and Takeda (all to institution). JGA reports personal fees and non-financial support from msd, personal fees from bms, personal fees from boehringer ingelheim, personal fees from amphera, personal fees from eli-lilly, personal fees from takeda, personal fees from bayer, personal fees from roche, personal fees from astra zeneca, outside the submitted work; In addition, JGA has a patent allogenic tumor cell lysate licensed to amphera, a patent combination immunotherapy in cancer pending, and a patent biomarker for immunotherapy pending. JAB reports reimbursement from Bristol-Myers Squibb and F Hoffmann-La Roche for the Netherlands Cancer Institute, and financial support for an investigator initiated trial from Merck Sharp & Dohme. CJG, VvdN, JAS, BB, NvW, RvH, MYES, AJS, WAB, GPB, FD, HvT, FL declare no competing interests. Ethics Approval Statement: The research protocol has been approved by the central ethical committee and local institutional review boards. All patients provided written informed consent.

Retrospective Analysis of S-1 plus Bevacizumab as Maintenance Therapy after Induction of S-1 and Oxaliplatin (SOX) plus Bevacizumab as First-Line Chemotherapy in Patients with Metastatic Colorectal Cancer

Background: The SOFT study was a phase III trial designed to validate the non-inferiority of S-1 and oxaliplatin (SOX) plus bevacizumab to mFOLFOX6 plus bevacizumab in terms of PFS in patients with metastatic colorectal cancer (mCRC) who had not previously received chemotherapy. In this study, we retrospectively reviewed cases in which S-1 plus bevacizumab as maintenance therapy after induction of S-1 and Oxaliplatin (SOX) plus bevacizumab as first-line chemotherapy in patients with metastatic colorectal cancer was applied in order to evaluate its efficacy and safety in clinical practice. Material and method: Among the 40 patients with mCRC at the Fuchu Hospital who received SOX plus bevacizumab as a first line treatment between August 2013 and December 2018. The eligible patients had histologically confirmed mCRC. On day 1 of each 3-week period during the study, patients in the SOX plus bevacizumab received a 7.5 mg/kg intravenous infusion of bevacizumab, followed by an intravenous infusion of 130 mg/m2 oxaliplatin. S-1 (40 - 60 mg) was administered orally two times per day from after dinner on day 1 to after breakfast on day 15, followed by a 7-day rest. Results: The median PFS was 15.0 months and median OS was 36.0 months. The response rate (RR: complete pus partial response) was 85.0%, and the disease control rate (DCR: RR plus stable disease) was 92.5%. The most common adverse events with SOX plus bevacizumab were hypertension (50%), neurosensory toxicity (50%), anorexia (32.5%), fatigue (45%), pigmentation (39%), Neutrophil count decreased (30%), and platelet count decreased (40%). The most common grade 3/4 adverse events were neurosensory toxicity (5%) and fatigue (9%). Conclusion: This study revealed that the survival benefit of S-1 and oxaliplatin (SOX) plus bevacizumab in Japanese patients with mCRC was like that observed in previous clinical trials. Therefore, S-1 and oxaliplatin (SOX) plus bevacizumab can be considered as routine first-line treatment option for patients with mCRC.

Retrospective analysis of the efficacy of cytokine-induced killer cell immunotherapy combined with first-line chemotherapy in patients with metastatic colorectal cancer.

ObjectivesFluoropyrimidine‐based chemotherapy regimens are the current first‐line treatment for metastatic colorectal cancer (mCRC); however, the outcome is often unsatisfactory. The present study aimed to determine the effect of combined cytokine‐induced killer (CIK) cell immunotherapy and first‐line chemotherapy in patients with mCRC.MethodsThis retrospective study included 252 patients with mCRC treated with first‐line chemotherapy. Among them, 126 patients received first‐line chemotherapy only (control group), while the other 126 patients, with similar demographic and clinical characteristics, received CIK cell immunotherapy combined with first‐line chemotherapy (CIK group). Overall survival (OS) and progression‐free survival (PFS) were compared between the two groups using the Kaplan–Meier method.ResultsThe median OS for the CIK group was 54.7 versus 24.1 months for the controls, and the median PFS for the CIK group was 25.7 versus 14.6 months for the controls. Univariate and multivariate analyses indicated that CIK cell treatment was an independent prognostic factor for patients' OS and PFS. Subgroup analyses showed that CIK cell treatment significantly improved the OS and PFS of patients with metastatic colon cancer, but not those with metastatic rectal cancer. Additionally, the change in CD3+CD56+ subsets after the fourth treatment cycle might be an indicator of successful CIK cell treatment: Patients with increased CD3+CD56+ subsets had better survival than those with decreased CD3+CD56+ subsets.ConclusionCytokine‐induced killer cell immunotherapy combined with first‐line chemotherapy could significantly improve the OS and PFS of patients with mCRC, particularly for patients with metastatic colon cancer.

Cost-effectiveness of adding atezolizumab to first-line chemotherapy in patients with advanced triple-negative breast cancer

Background:The effectiveness of atezolizumab plus nab-paclitaxel for advanced triple-negative breast cancer (TNBC) has been demonstrated. We aimed to evaluate its cost-effectiveness on advanced TNBC from the US payer perspective.Methods:A Markov model was adopted to project the disease course of newly diagnosed advanced TNBC. The clinical data were gathered from the IMpassion130 trial. Cost and health preference data were derived from the literature. The incremental cost-effectiveness ratio (ICER) was measured, and one-way sensitivity analysis and probabilistic sensitivity analysis were performed for exploring the model uncertainties.Results:Our results demonstrated that atezolizumab plus nab-paclitaxel augmented versus nab-paclitaxel therapy cost $104,278 and $149,465 and yielded an additional 0.371 and 0.762 of quality-adjusted life year (QALY) in in all patients with unknown PD-L1 status and subpopulation with PD-L1-positive, respectively, which led to an ICER of $281,448 and $196,073 per QALY gained. In all patients with unknown PD-L1 status, atezolizumab plus nab-paclitaxel treatment guiding by PD-L1 expression testing resulted in an ICER of $183,508 per QALY gained. Atezolizumab plus nab-paclitaxel could maintain a trend of positive incremental net health benefits and >50% probabilities of cost-effectiveness at the threshold of $200,000/QALY in more than half of subgroups with PD-L1-positive. One-way and probabilistic sensitivity analyses revealed the results were most sensitive to the hazard ratios (HRs) of overall survival (OS) of atezolizumab plus nab-paclitaxel versus nab-paclitaxel treatment.Conclusion:The atezolizumab plus nab-paclitaxel treatment is likely to be a cost-effective option compared with chemotherapy based on nab-paclitaxel for the patients with PD-L1-positive advanced TNBC.

A Real-World Study in Advanced Non–Small Cell Lung Cancer with KRAS Mutations

BACKGROUND: KRAS gene mutations are well known as a key driver of advanced non–small cell lung cancer (NSCLC). The impact of KRAS-mutant subtypes on the survival benefit from salvage chemotherapy is controversial. Here, we present a real-world study in patients across China with advanced NSCLC with KRAS mutations using a website-based patient self-report system. METHODS: We identified a total of 75 patients diagnosed with KRAS-mutant (determined by molecular sequencing) advanced NSCLC between 2014/5/9 and 2019/5/30. KRAS mutation subtypes were divided into G12C and non-G12C groups for statistical analysis. The clinicopathological characteristics and treatment survival benefit in all patients with a KRAS mutation were evaluated. Programmed death-ligand 1 (PD-L1) expression data were collected from 30 patients in the same cohort. RESULTS: In this study, 23 patients with stage IIIB NSCLC and 52 patients with stage IV NSCLC were enrolled with 58 men and 17 women; the median age was 60 years (39–84). All patients received regular chemotherapy/radiotherapy/targeted therapy/immune therapy as per the disease condition. Four main KRAS mutation subtypes were detected: G12C (33%), G12V (19%), G12A (12%), and G12D (12%). Three predominant KRAS comutations were detected: TP53-KRAS (31%), EGFR-KRAS (11%), and STK11-KRAS (8%). Compared with the KRAS non-G12C mutation subtype, patients with the KRAS G12C mutation had potentially longer progression-free survival (PFS) after first-line chemotherapy (4.7 vs. 2.5 months, p < 0.05). Pemetrexed-based chemotherapy appeared to be superior to taxanes- and gemcitabine-based chemotherapies in all patients (PFS: 5.0 vs. 1.5 and 2.3 months, respectively, p > 0.05). Cox regression analysis showed that the KRAS G12C mutation and pemetrexed-based first-line chemotherapy were positive influencers for PFS after first-line (hazard ratios = 0.31 and 0.55, respectively, P < 0.05), but not second-line chemotherapies. CONCLUSION: The KRAS G12C mutation could be a predictive biomarker for better survival benefit from first-line chemotherapy in patients with advanced NSCLC and KRAS mutations. The first-line chemotherapy regimen could possibly influence the outcome in patients with KRAS mutations. Larger and prospective clinical trials are warranted to confirm our conclusions.

Effects of adding necitumumab to first-line chemotherapy in patients with stage IV non-small-cell lung cancer: Meta-analysis.

Almost half of patients with non-small-cell lung cancer (NSCLC) are diagnosed at an advanced stage. Our aim was to assess the effects of adding necitumumab to chemotherapy in patients with stage IV NSCLC. A comprehensive literature search was performed according to pre-specified inclusion and exclusion criteria. Data on overall survival, progression-free survival, objective response rate and adverse events were extracted. A meta-analysis was performed to obtain pooled hazard ratios (HR) and corresponding 95% confidence intervals (CI) for time-to-event data and pooled odds ratio (OR) with 95% CI for dichotomous outcomes. The meta-analysis included four randomized clinical trials with 2074 patients. The pooled results showed significant improvement for overall survival (HR = 0.87 (95% CI 0.79-0.95), p = 0.004) when necitumumab was added to chemotherapy in patients with advanced NSCLC. No statistically significant improvement was noted for progression-free survival and objective response rate (HR = 0.83 (95% CI 0.69-1.01), p = 0.06 and OR = 1.46 (95% CI 0.90-2.38), p = 0.13, respectively). Subgroup analysis showed that in patients with non-squamous NSCLC, there was no benefit in overall survival and objective response rate. Patients with advanced NSCLC who received necitumumab were at the highest odds of developing a skin rash (OR = 14.50 (95% CI 3.16-66.43), p = 0.0006) and hypomagnesaemia (OR = 2.77 (95% CI 2.23-3.45), p < 0.00001), while the OR for any grade ≥3 adverse event was 1.55 (95% CI 1.28-1.87, p < 0.00001). The addition of necitumumab to standard chemotherapy in a first-line setting in patients with stage IV NSCLC results in a statistically significant improvement in overall survival, while the results were not significant for progression-free survival and objective response rate.

Association of XPD Asp312Asn polymorphism and response to oxaliplatin-based first-line chemotherapy and survival in patients with metastatic colorectal cancer.

Identification of biomarkers predicting a response to chemotherapeutic drugs would greatly ease the selection of personalized therapy. The protein xeroderma pigmentosum group D (XPD) functions in nucleotide excision repair (NER) to remove DNA cross-links and in the regulation of transcription. The potential role of the Asp312Asn polymorphism in predicting the response to chemotherapy has not been established. This prospective study was designed to determine the role of the XPD Asp312Asn polymorphism in predicting the response to oxaliplatin-based first-line chemotherapy and survival in patients with metastatic colorectal cancer. A total of 106 patients treated with 2 cycles of either FOLFOX4 (n = 72) or XELOX (n = 34) regimen as the chemotherapy were enrolled. The genotype of XPD Asp312Asn polymorphism was analyzed using TaqMan probe-based real-time polymerase chain reaction (PCR). Logistic regression was applied to predict the response to treatment protocols. Cox regression models were applied to predict overall survival. The overall response to chemotherapy was 57.6% (61/106). FOLFOX4 and XELOX regimens demonstrated comparable efficacy. The XPD Asp312Asn polymorphism was not associated with the response to either FOLFOX4 or XELOX regimen in univariate and in multivariate logistic regression analyses. Levels of carcinoembryonic antigen (CEA) ≥5 ng/mL and female gender were associated with a lack of response to FOLFOX4, but not to XELOX regimen. In a multivariate survival analysis, XPD Asp312Asn AA genotype, lack of response to chemotherapy, CEA ≥ 5 ng/mL, and age ≥65 were significantly associated with worse overall survival. The XPD Asp312Asn polymorphism is associated with overall survival, but it is not a biomarker in predicting the response to oxaliplatin-based first-line chemotherapy in patients with metastatic colorectal cancer.

A Study of IMP4297 as Maintenance Treatment Following First-line Chemotherapy in Patients With Advanced Ovarian Cancer

A Study of IMP4297 as Maintenance Treatment Following First-line Chemotherapy in Patients With Advanced Ovarian Cancer

Impact of Socioeconomic Factors on Timeliness of First Line Chemotherapy and Survival in Patients with Active Multiple Myeloma

Background Multiple myeloma is a common hematological malignancy. In 2016, there were an estimated 131,392 people living with myeloma in the United States and accounted for 2% of all cancer related deaths. Studies among cancer patients have repeatedly demonstrated that sociodemographic factors impact timeliness of treatment and in turn, survival (Kelly et al. Blood,2016). The treatment options in multiple myeloma are variable and may involve stem cell transplant , chemotherapies and biological therapies. We hypothesized that sociodemographic factors impact the time to initiation of first line chemotherapy in patients with multiple myeloma. We also explored if these factors influenced outcomes. Methods We queried the National Cancer Database for patients with multiple myeloma (ICD-0-3 code 9732) diagnosed from 2004-2016. We excluded patients who were considered for stem cell transplant or other modalites to include only those who received chemotherapy as first line treatment. Active myeloma patients were defined as those who were treated within 3 months (120 days) of diagnosis based on similar methodology in previous studies (Ravindran et al. Blood Cancer J,2016). Time to initiation (TTI) was defined as time in days (d) from diagnosis to initiation of systemic chemotherapy.Survival was measured in terms of months (m) from the day of diagnosis. Stepwise negative binomial regression and Cox proportional hazard models were used for analysis. Results Of 160,900 patients with multiple myeloma, we identified 71,523 patients meeting the eligibility criteria. Median age was 68 (range 21-90) years and 55% were males. Median TTI was 19d (range 0-120d) and median overall survival was 34 months. Even though the TTI increased from 24d (2004) to 27d (2016) this was not significant when other variables were adjusted. The overall median survival improved by 10 months between 2004 and 2012 (28 months to 37 months). Determinants of increased TTI in a multivariate model included African American race (p-value &lt;0.005), not living in Urban area (p-value=0.02), having less comorbidities (p-value&lt;0.0005), being treated at an academic or research program (p-value&lt;0.0005) and are described in Table 1. Factors impacting survival in a multivariate model included year of diagnosis (p-value&lt;0.0005) and age (p-value&lt;0.0005) - positive relation, time to treatment (negative relation, p-value&lt;0.0005-Figure 1), race (Caucasians-32m vs. African Americans-38m, p-value&lt;0.0005), insurance status (Government-28m vs. Private-48m, p-value&lt;0.0005), socioeconomic status (lowest-32m vs. highest-37m, p-value=0.003), comorbidities (lowest-38m vs. highest-15m, p-value&lt;0.0005) , treatment facility (Comprehensive Community Cancer Center-31m vs. Academic Research Program-38m) and are described in Table 2. Conclusion The findings of the present study are twofold. First, while not as pronounced as in other cancer cohorts, disparities do exist in timeliness to chemotherapy initiation. The longer TTI in academic centers is interesting but may reflect a more complicated patient population. Second, shorter time to therapy does not necessarily lead to improved outcome, likely reflecting high risk features not captured by standard assessments. This is similar to other studies in hematological malignancies and supports the proposition that clinical trials should accommodate patients who need urgent therapy to detect treatment effects in high‐risk groups (Olszewski et al. Br J Hem,2018). Disclosures No relevant conflicts of interest to declare.

190P - Details of response with first-line gemcitabine and nab-paclitaxel therapy in patients with advanced pancreatic cancer

BackgroundThe combination of gemcitabine and nab-paclitaxel (GnP) has been established as the first-line chemotherapy in patients (pts) with metastatic pancreatic cancer (M-PC). However, the efficacy of the therapy in pts with borderline resectable PC (BR-PC) and locally advanced PC (LA-PC) is not clear. Although achieving R0 resection is one of the main target for these pts, the details of the response, such as the best time to evaluate the response is not clear. Therefore, we evaluated the details of response with GnP treatment. MethodsWe retrospectively reviewed the medical records of pts with BR-PC, LA-PC, and M-PC who received GnP as the first-line chemotherapy between January 2016 and April 2019 at six hospitals. We investigated time to response (TTR), duration of response (DoR), and depth of response (DpR). The response of the primary tumor and the metastases were evaluated separately in pts with M-PC. The response of the primary tumor was evaluated in all pts. ResultsA total of 47 pts were analyzed; the median age was 70 years, male was 66% and the number of pts with BR-PC/LA-PC/M-PC was 6%/26%/68%. The response rates of primary tumor and metastases were 40% and 31%, respectively. Among the pts with M-PC, seven had a partial response (PR) of the primary tumor without PR of metastases. The median TTR and time to best response of the primary tumor and metastases were 3.17 months (m) and 4.21 m (p = 0.191), and 4.11 m and 5.88 m (p = 0.724), respectively. The median DoR of the primary tumor and metastases were 5.36 m and 4.11 m, respectively (p = 0.277). The median DpR of the primary tumor and metastases were 28.3% and 15.3%, respectively (p = 0.733). The median progression-free survival and overall survival in M-PC pts with and without PR of the primary tumor were 8.48 m and 6.41 m (p = 0.267), and 14.72 m and 7.66 m (p = 0.186), respectively. ConclusionsThe response of the primary tumor tended to be higher and earlier than that of the metastases. A favorable efficacy was observed in pts with BR-PC and LA-PC as well as pts with M-PC. This study indicated that the best time to evaluate the response of the primary site to consider the conversion therapy was around 4 m. Pts with M-PC showing PR of the primary tumor tended to have a favorable prognosis. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

EP1.12-07 High Discrepancy of Chemotherapy Outcomes Between Patients with Peripheral and Central Small Cell Lung Cancer

Previously we found that imaging central and peripheral LCNEC has distinct clinicopathologic features and survival. As LCNEC and SCLC are all neuroendocrine tumor, this study further investigated whether imaging tumor location impact the outcome of first line chemotherapy in patients with small cell lung cancer extensive disease. Patients with ES-SCLC diagnosis between May 2014 and September 2015 in Shanghai Pulmonary Hospital, Tongji University were included. Contrast enhanced CT scans were reviewed retrospectively for tumor location (central or peripheral) and imaging features. The clinical characteristics and outcomes of chemotherapy were collected and compared. 140 patients were identified with a median age of 64, 89.3%, 76.4% and 98.6% were male, smokers and ECOG PS 1 respectively. Among them, 135 received etopside based chemotherapy and 5 received irinotecan based chemotherapy.111 (79.3%) had central-type and 29 (20.7%) had peripheral-type SCLC. The patients characteristics were similar between the central and peripheral subgroups. Peripheral subgroup showed less marginal GGO (65.5% vs 84.7%, p=0.02), obstructive pneumonia (48.3% vs 80.2%, p=0.001), obstructive atelectasis (3.4% vs 40.5%, p<0.001) and effusion (37.9% vs 61.3%, p=0.011) than central tumors. Peripheral subgroup had lower ORR (44.8% vs 73%, p=0.004) and DCR (79.3% vs 92.8%, p=0.042). The median PFS was 4.6 months in the entire cohort and peripheral subgroup had significantly short PFS than central one (median PFS: 3.4 vs 5.1 months, p=0.001, figure A). The median OS was 12.9 months and peripheral subgroup had numerally short OS (median 11.6 vs 13.3 months, p=0.266, figure B). Central type tumors account for most of SCLC, while patients with peripheral tumors had a significantly lower ORR, shorter PFS and OS after the first line chemotherapy than central type.

854P - Updated survival analyses of 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)

BackgroundD 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. MethodsEligibility criteria included mCRPC diagnosis, ECOG PS≤2, adequate renal, hepatic and hematological functions, no prior treatment for mCRPC. Pts were randomized to receive D 75mg/m2 IV d1 q3w plus prednisone 5mg PO BID for 8 courses alone or plus E 160mg 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. ResultsBetween 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<0.0001). No differences were observed in terms of objective response rate. Major haematological toxicities consisted of grade 3-4 neutropenia (19 pts DE – 15 pts D); febrile neutropenia was observed in 10 DE pts and in 7 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). ConclusionsThe 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 identificationNCT02453009. Legal entity responsible for the studyThe authors. FundingAstellas. DisclosureO. Caffo: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: AstraZeneca. D. Gasparro: Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Astellas; Speaker Bureau / Expert testimony: Pfizer. R. Iacovelli: Advisory / Consultancy: Astellas; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Janssen; Advisory / Consultancy: Novartis. U.F.F. De Giorgi: Advisory / Consultancy: Astellas; Advisory / Consultancy: Bayer; Advisory / Consultancy: BMS; Advisory / Consultancy: Janssen; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi. G. Pappagallo: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy: Genzyme; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self): Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self): Roche. M. Aglietta: Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: Novartis; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self): PharmaMar; Travel / Accommodation / Expenses: Tesaro. All other authors have declared no conflicts of interest.

1024P - Phase II study: Letrozole maintenance therapy after first-line chemotherapy in patients with advanced serous and endometrioid ovarian cancer

BackgroundThe role of hormonal therapy in the treatment of advanced ovarian cancer (OC) has not been determined yet. Recently the hormone maintenance therapy (HMT) has been actively discussed. Methods70 patients (pts) with serous and endometrioid OC stage Ic-IV after 1st line chemotherapy (CT) with paclitaxel/platinum agents and complete (CR) or partial response (PR) were enrolled in phase II study. Pts received HMT with letrozole 2,5mg per day for 5 years or until disease progression. 71 pts with the same criteria who observed after 1st line CT was taken as retrospective control group. The groups were comparable at baseline including BRCA1/2 status. Paraffin-embedded material (N=141) after cytoreductive surgery was assessed for presence of estrogen/progesterone receptors (ER/PR) (IGH) and Ki67 in both groups. ResultsMedian progression-free survival (PFS) and overall survival (OS) after letrozole maintenance were 18.7 and 51.2 months respectively. In retrospective analysis PFS was significantly longer in letrozole group than in observational group (18.7 and 16.9 months, p=0.05; HR 0.68, 95%CI 0.44-0.98). There was no any significant difference in overall survival in HMT and observational groups. In the observational group 26 (36,6%) pts received hormone therapy for disease progression later. The expression of ER, PR and Ki67 didn’t have any prognostic and predictive role. Multivariate Cox regression analysis for PFS showed that administration of HMT, stage and response after CT associated with significantly longer PFS. Based on subgroup analysis only pts with stage III-IV with CR after 1st line had significantly longer PFS than pts who underwent observation: 20.9 vs 17.7 months (p=0.05; HR 0.56, 95%CI 0.32-0.99). ConclusionsHMT with letrozole could be effective in pts with advanced serous and endometriod OC stage III-IV with CR after 1st line CT regardless of tumour grade. Further randomized studies of HMT are needed. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

716P - FOLFOXIRI versus FOLFIRINOX in first-line chemotherapy in patients with advanced pancreatic cancer: A propensity score analysis

BackgroundAdvanced pancreatic ductal adenocarcinoma (aPDAC) remains a challenging, non-curable disease. FOLFIRINOX regimen is the standard in first-line chemotherapy (L1) in this setting. FOLFOXIRI, a similar schedule with a lower dose of irinotecan and no bolus 5-fluorouracil, has demonstrated efficacy and good tolerance in metastatic colorectal cancer. We aimed to compare clinical outcomes of this two regimens in patients with aPDAC in routine clinical practice. MethodsAnalyses were derived from all consecutive aPDAC patients treated in L1, between 2011 and 2017 in two French institutions, with FOLFOXIRI (n=165) or standard (n=124) regimens. FOLFOXIRI consisted of irinotecan (165mg/m2), oxaliplatin (85mg/m2), leucovorin (200mg/m2) and 5-fluorouracil (3200mg/m2 as a 48-hour continuous infusion) every two weeks. One hundred pairs of patients were selected through propensity score matching (PSM) analysis and clinical outcomes of the two treatments were compared. ResultsAfter a median follow up of 44.1 months, median overall survival (OS) was 11.1 months (95% confidence interval [CI], 9.8 to 13.1) in the FOLFOXIRI group and 11.6 months (95% CI, 10.8 to 15.5) in the FOLFIRINOX group. Median progression free survival (PFS) was 5.8 months (95% CI, 3.9 to 6.9) in the FOLFOXIRI group and 6.7 months (95% CI, 6.0 to 7.7) in the FOLFIRINOX group. After PSM, the survival of patients remained similar between the two regimens in OS (hazard ratio [HR], 0.79; 95% CI, 0.58 to 1.08; P=0.137) and PFS (HR, 0.80; 95% CI, 0.60 to 1.08; P=0.139). The objective response rate was 33.3% in the FOLFOXIRI group versus 47.2% in the FOLFIRINOX group, while disease-control rates were 62.8% and 75.3%, respectively (P=0.129). The grade 3 or 4 toxicities were occurring in 29.0% of patients in FOLFOXIRI group versus 21.3% in FOLFIRINOX group (P=0.216). FOLFOXIRI was associated with a higher incidence of grade 3 or 4 digestive adverse events compared to FOLFIRINOX group (11.0% versus 5.0%, respectively) but was similar to the safety profile of FOLFIRINOX previously reported in the PRODIGE 4/ACCORD 11 trial. ConclusionsFOLFOXIRI is feasible in L1 in patients with aPDAC but does not confer any therapeutic benefit as compared with FOLFIRINOX regimen. Legal entity responsible for the studyBesançon University Hospital. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

LBA92 - Switch maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma: A multicenter open label phase II trial (NVALT19)

BackgroundAll malignant mesothelioma (MM) patients progress after first-line therapy. We examined whether switch maintenance gemcitabine in patients, who did not show progression after first-line platinum-pemetrexed, could prolong time to disease progression. MethodsNVALT19 was an open label, randomized phase II trial, conducted in The Netherlands. Main eligibility criteria were pathologically proven MM, ECOG-PS 0-2 and completion of 4-6 cycles of first-line platinum-pemetrexed without progression. Patients were randomized 1:1 between gemcitabine (1250mg/m2day 1 and 8 of 3 weekly schedule) or best supportive care (BSC). Gemcitabine was given until disease progression, severe toxicity or patient request for discontinuation. Primary endpoint was progression free survival (PFS) determined by local physician according to modified RECIST (mRECIST) or death in the intention-to-treat population. It was computed that 118 events would yield 90% power to detect an increase in PFS from median 3.5 months to median 6 months at 90% confidence level. ResultsBetween March 2014 and February 2019, 130 patients were randomized, 65 in each arm. PFS was significantly longer with gemcitabine (median 6.2 months [range 4.6-8.7m]) than in the BSC arm (3.2 [2.8-4.2m]; hazard ratio 0.42; 95% confidence interval [CI], 0.28-0.63; p<0.0001). The PFS probability at 12 months was 25% for Maintenance Gemcitabine (95% CI: 16.3 - 38.5%) and 3.3% for BSC (95% CI: 0.8 - 13%). Central revision of PFS, by a blinded radiologist, also showed significant benefit for gemcitabine (median 5.3 months [4.2-7.1m]) above BSC (2.8 [2.5-3.3m]; hazard ratio 0.42; 95% CI 0.28 to 0.62; p<0.0001). Grade 3-4 adverse events (AE) occurred more in the gemcitabine arm (57% of patients) vs 13% in the BSC-arm. Neutropenia (22%), nausea (6%) and lung infection (5%) were most common treatment related grade III AE’s. Three patients (5%) experienced grade IV neutropenia. One patient died in the gemcitabine arm due to treatment related sepsis. Data on dose intensity will follow at ESMO 2019. ConclusionsSwitch maintenance gemcitabine after first-line chemotherapy significantly improves the PFS in malignant mesothelioma, with a manageable toxicity profile. Clinical trial identificationNTR4132. Legal entity responsible for the studyStichting NVALT studies. FundingDutch Cancer Society and Stichting NVALT studies. DisclosureAll authors have declared no conflicts of interest.

Overall survival results of AGO-OVAR16: A phase 3 study of maintenance pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced ovarian cancer

ObjectiveThe AGO-OVAR16 study was designed to test the efficacy, safety, and tolerability of pazopanib maintenance after first-line chemotherapy in patients with newly diagnosed advanced ovarian cancer (AOC). MethodsNine hundred and forty patients with histologically confirmed AOC, International Federation of Gynecology and Obstetrics (FIGO) stage II–IV, were randomized in a 1:1 ratio to receive either 800 mg pazopanib once daily or placebo for up to 24 months, unless there was disease progression, toxicity, withdrawal of consent, or death. The primary endpoint (investigator-assessed progression-free survival [PFS]) was met and previously reported. The results of final analyses of overall survival (OS) are reported here. ResultsA third OS interim analysis showed futility and led to study closure and a final OS analysis after last patient last visit. At the time of the final OS analysis, 494 (89.7% of the planned 551) events had occurred. No difference was observed in OS between pazopanib and placebo. The hazard ratio (HR) was 0.960 (95% confidence interval [CI]: 0.805–1.145), and the median OS from randomization was 59.1 months in pazopanib and 64.0 months in placebo arms. For the East Asian patients, similar to the first three interim OS analyses, a numerical negative trend was observed favoring placebo (HR, 1.332; 95% CI: 0.863–2.054). Exploratory analyses showed a trend for a longer time to first subsequent anti-cancer therapy or death with pazopanib over placebo (HR, 0.829; 95% CI: 0.713–0.965), with a median estimate of 19.0 and 14.5 months, respectively. No new safety signals were observed. ConclusionAlthough pazopanib prolonged PFS, this was not associated with improvement in median OS.Clinical trial information.ClinicalTrials.gov: NCT00866697.

Plasma exosomal microRNA-125b as a monitoring biomarker of resistance to mFOLFOX6-based chemotherapy in advanced and recurrent colorectal cancer patients.

Liquid biomarkers for the early detection of resistance to chemotherapy are important for improving prognosis. This study investigated the usefulness of plasma exosomal microRNA-125b (ex-miRNA-125b) for the early detection of resistance to modified fluorouracil, leucovorin and oxaliplatin (mFOLFOX6)-based first-line chemotherapy in patients with advanced or recurrent (advanced/recurrent) colorectal cancer (CRC). First, ex-miRNAs associated with resistance to mFOLFOX6-based chemotherapy were profiled via miRNA microarray analysis. In this analysis, ex-miR-125b exhibited the greatest upregulation in patients with progressive disease (PD) compared with the findings for patients with stable disease (SD) and healthy controls. Next, another 55 patients with advanced/recurrent CRC who received mFOLFOX6-based first-line chemotherapy underwent a validation study of ex-miR-125b. Blood samples were collected before and during treatment until tumor progression. Ex-miRNA levels were measured via TaqMan microRNA assays. Patients with CRC had significantly higher ex-miR-125b levels than healthy controls. In patients with partial responses, ex-miR-125b levels at the Response Evaluation Criteria in Solid Tumors (RECIST) judgment point were significantly lower than those measured before treatment. In patients with SD, ex-miR-125b levels did not differ before and during treatment. In patients with PD, ex-miR-125b levels at the RECIST judgment point were significantly higher than those measured before treatment. These changes in ex-miR-125b levels were significantly different between groups even 1 month after the initiation of chemotherapy. Progression-free survival (PFS) was significantly worse in patients with high baseline ex-miR-125b levels than in those with low levels. In the Cox analysis, baseline ex-miR-125b levels and KRAS mutation were indicated to be independent prognostic factors for PFS. The present results suggest that plasma ex-miR-125b levels may be useful for the early detection of resistance to mFOLFOX6-based first-line chemotherapy. Furthermore, ex-miR-125b before chemotherapy is a predictive biomarker for PFS in patients with advanced/recurrent CRC.

Fluoropyrimidine with or without platinum as first-line chemotherapy in patients with advanced gastric cancer and severe peritoneal metastasis: a multicenter retrospective study

BackgroundThere is no standard first-line chemotherapy for advanced gastric cancer with severe peritoneal metastasis. Although fluoropyrimidine is often used, its efficacy is limited, and it remains unclear whether combination therapy with platinum improves clinical outcomes.MethodsThis retrospective study involved patients at six Japanese academic hospitals between 2010 and 2016. Patients with advanced gastric cancer and severe peritoneal metastasis were included if they had massive ascites and/or inadequate oral intake requiring intravenous nutritional support. We then compared the efficacy and safety of fluoropyrimidine monotherapy with those of fluoropyrimidine/platinum combination therapy.ResultsCompared with the combination therapy group (n = 64), the monotherapy group (n = 65) had worse general health (more patients with elderly age, performance status > 2, and having both massive ascites and inadequate oral intake). Both overall survival (9.0 vs 5.0 months, p < 0.01) and progression-free survival (4.3 vs 2.3 months, p < 0.01) were significantly longer in the combination group, and the significance remained after adjusting for prognostic variables (hazard ratios of 0.47 and 0.41, respectively; p < 0.01). Improvements in ascites and oral intake were also greater in the combination group. Although neutropenia (grade ≥ 3) occurred more frequently with combination therapy, both treatments in this study were tolerable.ConclusionsCombination therapy with fluoropyrimidine and platinum might be more effective than monotherapy with fluoropyrimidine and was tolerable for patients with advanced gastric cancer and severe peritoneal metastasis.

Targeting the PI3-kinase pathway in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is characterised by poor outcomes and a historical lack of targeted therapies. Dysregulation of signalling through the phosphoinositide 3 (PI3)-kinase and AKT signalling pathway is one of the most frequent oncogenic aberrations of TNBC. Although mutations in individual genes occur relatively rarely, combined activating mutations in PIK3CA and AKT1, with inactivating mutations in phosphatase and tensin homologue, occur in ∼25%‒30% of advanced TNBC. Recent randomised trials suggest improved progression-free survival (PFS) with AKT-inhibitors in combination with first-line chemotherapy for patients with TNBC and pathway genetic aberrations. We review the evidence for PI3K pathway activation in TNBC, and clinical trial data for PI3K, AKT and mammalian target of rapamycin inhibitors in TNBC. We discuss uncertainty over defining which cancers have pathway activation and the future overlap between immunotherapy and pathway targeting.

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)