Patients For First-line Treatment Research Articles

Neutrophil-to-lymphocyte ratio as a prognostic marker in highly PD-L1 expressing advanced non-small cell lung cancer patients in first line treatment with pembrolizumab

Neutrophil-to-lymphocyte ratio as a prognostic marker in highly PD-L1 expressing advanced non-small cell lung cancer patients in first line treatment with pembrolizumab

Pharmacokinetics, safety, tolerability, and feasibility of apatinib in combination with gefitinib in stage IIIB-IV EGFR-mutated non-squamous NSCLC: a drug-drug interaction study.

Apatinib combined with gefitinib was proven to benefit advanced EGFR-mutant NSCLC patients in first-line treatment. This study aimed to evaluate the drug-drug interaction of gefitinib and apatinib when coadministered in EGFR-mutated NSCLC patients. In this phase 1b, multi-center, open-label, fixed-sequence study, the drug-drug interaction of gefitinib and apatinib was evaluated when coadministered in EGFR-mutated NSCLC patients. Patients received single-agent apatinib 500mg QD on days 1-4. Gefitinib 250mg QD was given on days 5-15 and combined with apatinib 500mg QD on days 12-15. Serial blood samples were drawn on days 4 and 15. The plasma concentrations and other pharmacokinetics parameters were measured for apatinib with and without gefitinib. The study enrolled 22 patients and 20 were analyzed for pharmacokinetics. There were no distinct differences in apatinib Cmax and AUC0-τ with versus without gefitinib (geometric LSM ratio, 0.96 [90% CI 0.84-1.10] for Cmax and 1.12 [90% CI 0.96-1.30] for AUC0-τ). Similar PFS and grade of treatment-emergent adverse events (TEAEs) were found between different Cmax and AUC0-τ of apatinib and gefitinib at 500mg apatinib and 250mg gefitinib dose levels. Apatinib pharmacokinetics parameters were not significantly changed when coadministered with gefitinib. All TEAEs were manageable, and there was no need to change the dose level when combining apatinib and gefitinib (ClinicalTrials.gov identifier: NCT04390984, May 18, 2020).

CPX-351 in higher risk myelodysplastic syndrome and chronic myelomonocytic leukaemia: a multicentre, single-arm, phase 2 study

CPX-351, an encapsulated form of cytarabine and daunorubicin, has shown greater efficacy than the classic 3 + 7 treatment administration in secondary acute myeloid leukaemia. Given that higher-risk myelodysplastic syndrome and chronic myelomonocytic leukaemia share similarities with secondary acute myeloid leukaemia, we aimed to investigate the safety and efficacy of CPX-351 in this context. This investigator-initiated two-cohort phase 2 trial was conducted by the Groupe Francophone des Myélodysplasies, with 12 participating centres in France. It comprised cohort A (reported here and completed), which included patients in first-line treatment, and cohort B, which was stopped for lack of inclusion (ie, not enough patients met the inclusion criteria), for patients with hypomethylating agent failure that is not reported here. Cohort A enrolled patients with newly diagnosed higher-risk myelodysplastic syndrome or chronic myelomonocytic leukaemia (aged 18-70 years old) with an Eastern Cooperative Oncology Group performance status of 0-1. Intravenous CPX-351 (100 mg/m2 cytarabine and 44 mg/m2 daunorubicin) was given on days 1, 3, and 5, with a second induction cycle given (same daily dose on days 1 and 3) if at least a partial response was not reached. Patients who responded could receive up to four monthly consolidation cycles (same daily dose on day 1) or allogeneic haematopoietic stem-cell transplantation (HSCT). Overall response rate after one or two induction courses according to European LeukemiaNet 2017 acute myeloid leukaemia was the primary endpoint after CPX-351 induction, whether patients received one or two induction cycles. Safety was assessed in all patients enrolled (in cohort A). This trial is registered with ClinicalTrials.gov, NCT04273802. Between April 29, 2020, and Feb 10, 2021, 21 (68%) male and ten (32%) female patients were enrolled. 27 (87%) of 31 patients responded (95% CI 70-96). 16 (52%) of the 31 patients received at least one consolidation cycle. 30 (97%) of the 31 patients included were initially considered eligible for allogeneic HSCT and 29 (94%) of the 31 patients had the procedure. Median follow-up was 16·1 months (IQR 8·3-18·1). The most common grade 3-4 adverse events were pulmonary (eight [26%] of 31 patients) and cardiovascular (six [19%] of 31 patients). There were 14 serious adverse events (mainly hospitalisation for infection [n=5] and only one was treatment-related) and no treatment-related death. CPX-351 appears to be active and safe in patients with higher-risk myelodysplastic syndrome and chronic myelomonocytic leukaemia, allowing bridging to allogenic HSCT in most patients. Jazz Pharmaceuticals.

Abstract P4-01-38: A single arm phase II trial of Palbociclib in combination with Tamoxifen as first line therapy for metastatic hormone receptor positive breast cancer

Abstract Background: Palbociclib is a CDK4/6 inhibitor used to treat metastatic hormone receptor-positive (HR+) breast cancer (MBC) in combination with endocrine therapy. Tamoxifen is an effective treatment for HR+ MBC, with different toxicity profile compared with aromatase inhibitors (AI) and fulvestrant. Preclinical data demonstrated synergy for the combination of tamoxifen and palbociclib, being effective in a model of acquired tamoxifen resistance. Methods: We conducted a non-randomized, open-label, single-arm, multicenter, phase II trial of palbociclib in combination with tamoxifen in patients with HR+/HER2 - advanced BC, with no prior therapy for MBC. Ovarian suppression was recommended for pre-menopausal women. Primary objective was progression free survival, PFS. Secondary objectives: objective response rate, ORR (CR or PR) based on RECIST 1.1 or MDA Criteria (for patients with bone only disease); safety and tolerability (using CTCAE v4); clinical benefit rate, CBR (CR, PR or SD lasting min 24 weeks); 2-year overall survival. Correlative objectives: proteomic analysis of plasma exosomes to identify mechanisms of primary and secondary resistance to tamoxifen/palbociclib. Results: Between 6/30/2016 and 7/02/2019, we enrolled 49 patients (47 evaluable): 23 pts with de-novo metastatic disease and 24 pts with recurrent BC (12 pts were on adjuvant treatment with AI at time of recurrence and 12 pts on surveillance). As of 6/30/2022 data cut-off, 2 pts were still on treatment. This is an updated analysis with median follow-up time of 24 months (range 8-51). Median age was 60 (range 39-82). The median PFS was 19.8 months with 95% CI (8-41) for pts with de-novo MBC and 7 months (2-12) for pts with recurrent BC. The ORR was 30% overall, 39% for pts with de novo MBC, 21% for pts with recurrent BC. CBR was 64% overall, 77% for pts with de novo MBC and 50% for pts with recurrent BC. CBR was 65% for white pts and 55% for AA pts. Best response per RECIST1.1: 14 pts (34%) had PR, 18 pts (44%) had SD, 9 pts (22%) had PD. All 6 pts with bone only disease had SD. The most common drug related grade ≥ 3 AE was neutropenia (51%), transient and manageable by dose modifications, no cases of febrile neutropenia. Four patients (8%) developed thromboembolic events (grades 2, 3, 4) and discontinued treatment. One patient died while on treatment from PD. More than 800 exosome proteins were detected in the samples analyzed so far. Exosomal protein networks in pretreatment samples predicted treatment response with 89% sensitivity and 95% specificity in unsupervised clustering. Data on correlative objectives will be presented in a separate abstract. Conclusions: The combination of palbociclib and tamoxifen showed tolerable, expected safety profile. This may be an alternative approach for selected patients in first line treatment of HR+ MBC, especially those who present with de-novo metastatic disease and are intolerant to AI; although this small study indicates a lower PFS. Table 1: Baseline Demographics Citation Format: Oana C. Danciu, Kent Hoskins, Jennifer Weiss, Cristina I. Truica, Anne Blaes, Deimante Tamkus, Jatin Rana, Tandra Pavankumar, Lauren Green, Yu Gao, Menggang Yu, Qianqian Zhao, Deborah Toppmeyer, Ruth O’Regan, Kari B. Wisinski. A single arm phase II trial of Palbociclib in combination with Tamoxifen as first line therapy for metastatic hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-38.

Health-related quality of life of multiple myeloma patients after the first-line treatment: results of a prospective cohort study

Objective: The aim of this study was to evaluate whether there was an improvement or a deterioration of health-related quality of life (HRQoL) of multiple myeloma patients (MM), and to assess the associated factors with HRQoL after 12 months of treatment. Methods: We performed a prospective cohort study with MM patients in first-line treatment from public and private onco-hematology health services in a Brazilian metropolis. HRQoL, socio-demographic and clinical variables were obtained by interviews and review of medical charts. HRQoL and peripheral neuropathy (PN) were collected through validated instruments (QLQ-C30, QLQ-MY20, CINQ). Medians of the HRQoL scores, obtained at baseline and follow-up interviews, were compared. Median HRQOL scores at follow-up were compared by variables. The improvement or deterioration in HRQoL and the association with variables were measured. Results: Thirty-three patients completed the follow-up, with ISS III (25.0 %), on polypharmacy (72.2 %), using a thalidomide+bortezomib-based regimen as first-line (19.4 %), and median age of 66.5 years. HRQoL Summary score, Functioning, Symptom scales, and Future Perspective scores were improved between periods (p<0.05). Patients who were on polypharmacy, with severe PN, and with ISS III had deterioration in HRQoL; younger patients had improvement and older patients had deterioration in HRQoL (p<0.05). Conclusions: Our study showed that first-line treatment improved HRQoL of patients in the following QLQ-C30 scales: Summary score, Role functioning, Emotional functioning, Fatigue, Pain, and Constipation; and in QLQ-MY20, Future perspective was improved. Our study shows the importance of using patient-reported outcomes during MM treatment.

Gemcitabine Plus Anlotinib Is Effective and Safe Compared to Gemcitabine Plus Docetaxel in Advanced Soft Tissue Sarcoma.

ObjectiveThe aim of this study is to compare gemcitabine (G) plus docetaxel (D) versus G plus anlotinib (A) for advanced soft tissue sarcoma (STS).MethodsWe retrospectively investigated 122 patients with locally advanced or metastatic STS who were treated with either G+D or G+A between July 2016 and October 2021 and compared the efficacy and toxicity of G+D and G+A. The primary endpoints were median progression-free survival (PFS) and the proportion of patients with grade ≥3 adverse events. We also analyzed differences in the clinical efficacy of G+D and G+A in leiomyosarcoma, and the differences in the clinical efficacy of G+D and G+A as first-line therapy.ResultsOverall, 122 patients were included (81 patients receiving G+D and 41 patients receiving G+A) with a median age of 55 years. The main histological types are leiomyosarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma. After a median follow-up of 25 months, PFS did not differ between patients treated with G+D and those treated with G+A (median PFS: 5.8 months and 6.8 months, p = 0.39), and overall survival (OS) was similar (median OS: 14.7 vs. 13.3 months, p = 0.75) with a similar objective response rate (18.5% vs. 14.6%, p = 0.17), whereas the proportion of patients with grade ≥3 adverse events treated with G+D was significantly higher than those treated with G+A (68% vs. 44%, p < 0.05). Subgroup analysis of leiomyosarcoma patients (47.5% of the patients) and first-line treatment patients (46.7% of the patients) shows that PFS was not significantly different between the two groups (LMS: median PFS: 6.5 months vs. 7.5 months, p = 0.08; first-line treatment: median PFS: 6.2 months vs. 7.1 months, p = 0.51).ConclusionCompared with gemcitabine plus docetaxel for advanced STS, gemcitabine plus anlotinib achieved a similar response rate on median PFS and OS, but lower toxicity. These results suggest that gemcitabine plus anlotinib may be an effective and safe strategy for advanced STS.

Outcomes of Anlotinib Maintenance Therapy in Patients With Advanced NSCLC in a Real-World Setting.

BackgroundAnlotinib is a novel tyrosine kinase inhibitor with promising anti-tumor activity in patients with advanced non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the efficacy and safety of anlotinib maintenance therapy in patients with advanced NSCLC in real-world situation.MethodsWe conducted a retrospective study on the patients with stage IIIb or IV NSCLC who visited our hospital between December 2016 and April 2020. They achieved an objective response or stable disease after first- or second- line treatment and then received switch maintenance therapy with anlotinib. Data were collected using automated data mining technology from electronic health records. Patients’ demographic and clinical characteristics, median progression-free survival (PFS), median overall survival (OS), and adverse events were described, and preliminary analysis of efficacy predictors was analyzed.ResultsThirty-two patients were included in this study (20 patients in first-line treatment and 12 patients in second-line treatment). Median anlotinib maintenance time was 9 days (Q1-Q3: 3-22). The median PFS was 11.5 months, with 11.5 months in first-line treatment and 8.9 months in second-line treatment. The median OS was 12.0 months, with 16.4 months in first-line treatment group and 8.9 months in second-line treatment group. Grade 2-3 treatment-related adverse events were reported in 18.76% patients. No life-threatening adverse events were observed.ConclusionOur results suggested that anlotinib maintenance therapy might be a potentially safe and efficacious option for patients who had benefited from first- or second-line treatment. However, our data are limited representative due to the small sample size; the efficacy of anlotinib maintenance therapy warrants further evaluation.

What underlies the observed hospital volume-outcome relationship?

BackgroundStudies of the hospital volume-outcome relationship have highlighted that a greater volume activity improves patient outcomes. While this finding has been known for years, most studies to date have failed to delve into what underlies this relationship.ObjectiveThis study aimed to shed light on the basis of the hospital volume effect on patient outcomes by comparing treatment modalities for epithelial ovarian carcinoma patients.DataAn exhaustive dataset of 355 patients in first-line treatment for Epithelial Ovarian Carcinoma (EOC) in 2012 in three regions of France was used. These regions account for 15% of the metropolitan French population.MethodsIn the presence of endogeneity induced by a reverse causality between hospital volume and patient outcomes, we used an instrumental variable approach. Hospital volume of activity was instrumented by the distance from patients’ homes to their hospital, the population density, and the median net income of patient municipalities.ResultsBased on our parameter estimates, we found that the rate of complete tumor resection would increase by 15.5 percentage points with centralized care, and by 8.3 percentage points if treatment decisions were coordinated by high-volume centers compared to decentralized care.ConclusionAs volume alone is an imperfect correlate of quality, policy-makers need to know what volume is a proxy for in order to devise volume-based policies.

First-line pembrolizumab plus chemotherapy for extensive-stage small-cell lung cancer: a United States-based cost-effectiveness analysis

BackgroundThe clinical trial of Keynote-604 showed that pembrolizumab plus chemotherapy could generate clinical benefits for extensive-stage small-cell lung cancer (ES-SCLC). We aim to assess the efficacy and cost of pembrolizumab combined with chemotherapy in the first-line treatment setting of ES-SCLC from the United States (US) payers’ perspective.MethodsA synthetical Markov model was used to evaluate cost and effectiveness of pembrolizumab plus platinum-etoposide(EP) versus EP in first-line therapy for ES-SCLC from the data of Keynote-604. Lifetime costs life-years(LYs), quality adjusted LYs(QALYs) and incremental cost-effectiveness ratios(ICERs) were estimated. One-way and probabilistic sensitivity analyses were performed. Furthermore, we performed subgroup analysis.ResultsPembrolizumab plus EP resulted in additional 0.18 QALYs(0.32 LYs) and corresponding incremental costs $113,625, resulting an ICER of $647,509 per QALY versus EP. The price of pembrolizumab had a significant impact on ICER. Probabilistic sensitivity analysis indicated that pembrolizumab combined chemotherapy may become a cost-effective option with a probability of 0%. Besides, subgroup analysis suggested that all subgroups were not cost-effective.ConclusionFrom the perspective of the US payer, pembrolizumab plus EP is not a cost-effective option for first-line treatment patients with ES-SCLC at a WTP threshold of $150,000 per QALY.

Iadademstat in Combination with Azacitidine Generates Robust and Long Lasting Responses in AML Patients (ALICE Trial)

Iadademstat in Combination with Azacitidine Generates Robust and Long Lasting Responses in AML Patients (ALICE Trial)

Circulating tumor DNA-guided treatment with pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer: a phase 2 trial

The applicability of circulating tumor DNA (ctDNA) genotyping to inform enrollment of patients with cancer in clinical trials has not been established. We conducted a phase 2 trial to evaluate the efficacy of pertuzumab plus trastuzumab for metastatic colorectal cancer (mCRC), with human epidermal growth factor receptor 2 (HER2) amplification prospectively confirmed by tumor tissue or ctDNA analysis (UMIN000027887). HER2 amplification was confirmed in tissue and/or ctDNA in 30 patients with mCRC. The study met the primary endpoint with a confirmed objective response rate of 30% in 27 tissue-positive patients and 28% in 25 ctDNA-positive patients, as compared to an objective response rate of 0% in a matched real-world reference population treated with standard-of-care salvage therapy. Post hoc exploratory analyses revealed that baseline ctDNA genotyping of HER2 copy number and concurrent oncogenic alterations adjusted for tumor fraction stratified patients according to efficacy with similar accuracy to tissue genotyping. Decreased ctDNA fraction 3 weeks after treatment initiation associated with therapeutic response. Pertuzumab plus trastuzumab showed similar efficacy in patients with mCRC with HER2 amplification in tissue or ctDNA, showing that ctDNA genotyping can identify patients who benefit from dual-HER2 blockade as well as monitor treatment response. These findings warrant further use of ctDNA genotyping in clinical trials for HER2-amplified mCRC, which might especially benefit patients in first-line treatment.

Efficacy and safety of anti-vascular endothelial growth factor therapies in older patients for first line treatment of metastatic renal cell carcinoma.

Backgroundimmunotherapy became the first line treatment of metastatic renal cell carcinoma (mRCC). Nevertheless, a better understanding of the specificities of targeted therapies (TT) in the elderly population could be helpful in order to improve the management of mRCC in this population. The aim of this retrospective study was to assess efficacy and safety of sunitinib and sorafenib used as first-line TT in 70 years older patients compared to younger patients.MethodsData were retrospectively collected for all consecutive mRCC patients receiving first line TT treatment by sunitinib or sorafenib for mRCC from January 2006 to November 2017. Patients were divided into two groups according to the age using a cut-off at 70 years old. Median progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method and compared using log-rank test.ResultsIn total, 147 patients were included; 94 (63.9%) were <70 and 53 (36.1%) were 70 years old or more. First line TT used was sunitinib in 123 (83.7%) patients or sorafenib in 24 (16.3%) patients. Median PFS was 8 months for elderly patients vs. 6 in younger group (P=0.68). Median OS were 26 vs. 36 months (P=0.08). Severe induced toxicity was more frequent among elderly patients: 34 (64.2%) vs. 46 patients (48.9%) (P=0.07). Rate of treatment discontinuation due to toxicity was 22 patients (23.4%) in younger group vs. 28 patients (52.8%) in the elderly group (P=0.0005). Results were similar in the 2 groups regarding the type of toxicities.ConclusionsOur results suggest similar efficacy of anti-vascular endothelial growth factor (VEGF) agents as first-line treatment for mRCC among younger and older patients with an age cut-off of 70 years. Safety results suggest that these drugs can be safely used for older patients with a need of caution regarding toxicity prevention.

A single-arm phase II trial of palbociclib in combination with tamoxifen as first-line therapy for metastatic hormone receptor-positive breast cancer.

1056 Background: Palbociclib is a CDK4/6 inhibitor used to treat metastatic hormone receptor-positive (HR+) breast cancer (MBC) in combination with endocrine therapy. Tamoxifen is an effective treatment for HR+ MBC, with different toxicity profile compared with aromatase inhibitors (AI) and fulvestrant. Preclinical data demonstrated synergy for the combination of tamoxifen and palbociclib, being effective in a model of acquired tamoxifen resistance. Methods: We conducted an open-label, single-arm, multicenter phase II trial of palbociclib in combination with tamoxifen in patients with HR+/HER2 - advanced BC, with no prior therapy for MBC. Ovarian suppression was recommended for pre-menopausal women, but not required. Primary objective was progression free survival. Secondary objectives: objective response rate (CR or PR) based on RECIST 1.1 or MDA Criteria (for patients with bone only disease); safety and tolerability (using CTCAE v4); clinical benefit rate (CR, PR or SD lasting min 24 weeks); 2-year overall survival. Correlative objectives: proteomic analysis of plasma exosomes to identify mechanisms of primary and secondary resistance to tamoxifen/palbociclib. Results: Between 6/30/2016 and 7/02/2019, we enrolled 49 patients (47 evaluable): 23 pts with de-novo metastatic disease and 24 pts with recurrent BC (12 pts were on adjuvant treatment with AI at time of recurrence and 12 pts on surveillance). As of 1/5/21 data cut-off, 7 pts were still on treatment. Median follow-up time was 24 months (range 8-42). Median age was 60 (range 39-82). The median PFS was 14.6 months with 95% CI (7-41) for pts with de-novo MBC and 6 months (2-12) for pts with recurrent BC. The ORR was 30% overall, 39% for pts with de novo MBC, 21% for pts with recurrent BC. CBR was 64% overall, 78% for pts with de novo MBC and 50% for pts with recurrent BC. CBR was 65% for white pts and 55% for African American pts. Best response per RECIST1.1: 14 pts (34%) had PR, 18 pts (44%) had SD, 9 pts (22%) had PD. All 6 pts with bone only disease had SD. The most common drug related grade ≥ 3 AE was neutropenia (51%), transient and manageable by dose modifications, no cases of febrile neutropenia. Four patients developed thromboembolic events (1 grade 2, 2 grade 3, 1 grade 4). One patient died while on treatment from PD. Conclusions: The combination of palbociclib and tamoxifen showed tolerable, expected safety profile. This may be an alternative approach for selected patients in first line treatment of HR+ MBC, especially those who are intolerant to AI, although this small study indicates a lower PFS. Clinical trial information: 02668666 .[Table: see text]

Efficacy and safety of anti-PD-1-based therapy in combination with PARP inhibitors for patients with advanced solid tumors in a real-world setting

BackgroundRationale exists for combining immune checkpoint inhibitors and PARP inhibitors (PARPi), and results of clinical trials in ovarian cancer are promising, but data in other cancers are limited.MethodEfficacy and safety of PARPi/anti-PD-1 in advanced solid tumors were retrospectively analyzed. The efficacy measures included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS).ResultsThis retrospective study included data from 40 patients. The ORR was 27.5% (95% CI, 13.0–42.0%), with a DCR of 85.0% (95% CI, 73.4–96.6%). Except four patients in first-line treatment (three with PR and one with SD), the ORR of ≥second-line treatment, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) was 22.2%, 23.1% and 28.6%, and the DCR was 83.3%, 84.6% and 71.4%, separately. The median PFS of all patients, ≥second-line treatment, NSCLC and SCLC was 4.6 m, 4.2 m, 4.5 m and 3.7 m. The median OS was 9.4 m, 11.4 m, 12.7 m and 5.4 m, respectively. Multivariable analysis revealed that BRCA1/2 mutation was positively correlated with ORR (P = 0.008), and LDH≥250U/L was negatively correlated with lowered DCR (P = 0.018), while lymphocyte number, ECOG and LDH significantly influenced both PFS and OS. We found that the possible resistant mechanisms were sarcomatous degeneration and secondary mutation, including BRCA2 truncation mutation, A2M, JAK1,T790M, KEAP1 and mTOR mutation. 37.5% patients had ≥grade 3 adverse events.ConclusionPARPi/anti-PD-1 is an effective and tolerable method for patients with advanced solid tumors, and BRCA1/2 is a potential biomarker.

FP02.04 NSCLC with TPS&gt;90% could have Higher Possibility of Causing Severe irAE; Retrospective Investigation in one Institution

Recently, immune checkpoint inhibitors (ICI) have been introduced into clinical treatment strategy for advanced or recurrent NSCLC. However, little is known about the relation between the risk of irAE and patients’ clinical backgrounds. In this research, we attempted to reveal which types of clinical backgrounds are likely associated with the development of severe irAE when they were treated with ICI. We have treated over 300 advanced or recurrent NSCLC with ICI in our institute since January 2016, and the results of TPS were obtained in 240 patients. We retrospectively analyzed the relationship between patients’ clinical backgrounds and severe irAE which caused discontinuation of treatment. We excluded patients who were treated with durvalmab because it has different treatment strategy from other ICIs. Patients' background is shown below. We defined TPS>90% as ultra-high TPS, because those patients are shown to have preferable response to ICI. All the patients with EGFR mutation received EGFR-TKI before ICI.Tabled 1first-line groupsecond or later-line groupcharasteristicAge, yearsmedian71.970.2range (95% C.I.)70.2-73.668.9-71.6Sexfemale18 ( 18.9%)56 ( 38.6%)Male77 ( 81.1%)89 ( 61.4%)Histologic diagnosisadenocarcinoma48 ( 50.5%)89 ( 61.4%)squamouscarcinoma38 ( 40.0%)37 ( 25.5%)others9 ( 9.5%)19 ( 13.1%)ECOG performance statusgood (0 or 1)80 ( 84.2%)96 ( 76.8%)poor (2 -4)15 ( 15.9%)29 ( 23.2%)TPShigh expression (>50%)67 (70.5%)40 (27.6%)low expression (1-49%)22 (23.2%)56 (38.6%)negative (<1%)6 ( 6.3%)49 (33.8%)ultra-high expression (>90%)32 ( 33.7%)19 ( 13.1%)Driver mutationno92 ( 96.8%)105 ( 72.4%)yes3 ( 3.2%)40 ( 27.6%)EGFR / KRAS / HER2 / others0 / 2 / 1 / 036 / 1 / 2 / 1ICIpembrolizumab84 ( 88.4%)57 ( 39.3%)nivolumab0 ( 0%)62 ( 42.8%)atezolizumab11 ( 11.6%)26 ( 17.9%) Open table in a new tab Forty-six had severe irAE of any grade of ILD or >Grade3 AE, and most of them were treated with steroids. Nineteen of them received ICI subsequently. Univariate analysis indicated that TPS>50%, first-line treatment and administration of pembrolizumab showed significantly higher possibility of severe irAE (p<0.05, p<0.001, p<0.05, respectively). Furthermore, patients with ultra-high TPS was likely to experience severe irAE compared to other groups (p<0.01). When we examine the patients in first-line treatment, only ultra-high TPS showed statistically higher tendency of irAE (p<0.05). However, in second or later-line patients, no clinical backgrounds indicated the higher risk of irAE. No difference was observed in response rate between ultra-high and other group in first-line treatment (71.9%, 61.9% respectively, p=1.0). In later-line, ultra-high group showed better response rate than others (52.6%, 19.8% respectively, p=0.032). However, no differences were observed in time to treatment failure and OS between ultra-high and others. In 1st-line patients, TTF of ultra-high and others was 207days and 175days (p=0.306), OS was 727days and 742days, respectively (p=0.74). In later-line, TTF was 107days and 70days(p=0.109),and OS was 511days and 308days (p=0.448). Patients with ultra-high TPS had higher possibility of irAE especially when they received ICI for first-line. However, no difference was observed in OS between two groups. In our investigation, survival was not translated from better response in ultra-high group.

Prognostic role of a new inflammatory index with neutrophil-to-lymphocyte ratio and lactate dehydrogenase (CII: Colon Inflammatory Index) in patients with metastatic colorectal cancer: results from the randomized Italian Trial in Advanced Colorectal Cancer(ITACa) study.

Aim: The aim of this study was to investigate the role of a new inflammatory index (Colon Inflammatory Index [CII]) as a predictor of prognosis and treatment efficacy in patients with metastatic colorectal cancer (mCRC) enrolled in the prospective multicenter randomized ITACa (Italian Trial in Advanced Colorectal Cancer) trial to receive first-line chemotherapy (CT)+ bevacizumab or CT alone.Patients and methods: Between November 14, 2007 and March 6, 2012, 276 patients diagnosed with CRC were available for baseline neutrophil-to-lymphocyte ratio (NLR) and lactate dehydrogenase (LDH). We divided the population into three groups on basis of the CII index.Results: At baseline in all populations, median PFS and OS was predictive of clinical outcome (p<0.0001). Following adjustment for clinical covariates, multivariate analysis confirmed CII index as an independent prognostic factor. The CII index was also predictive when we evaluated the two distinct arms with (p=0.0009) or without bevacizumab (p=0.0001). When we divided right side versus left side for treatment regimen (CT plus bevacizumab versus only bevacizumab), we found a benefit of bevacizumab versus only CT in the right side in patients treated with bevacizumab and not in patients treated with only chemotherapy. Conversely, we found no difference the left side, but we found a difference in the poor group of 4 months in favor to only chemotherapy.Conclusion: Our results indicate that the CII index is a good prognostic marker for mCRC patients in first line treatment with CT with or without bevacizumab.Trial registration: NCT01878422 ClinicalTrials.gov; date of registration: June 7, 2013.

PCN223 - WHAT UNDERLIES THE OBSERVED HOSPITAL VOLUME-OUTCOME RELATIONSHIP?

Studies of the hospital volume-outcome relationship have highlighted that a greater volume activity improves patient outcomes. While this finding has been known for years in health services research, most studies to date have failed to delve into what underlies this relationship. This study aimed to shed light on the basis of the hospital volume effect by comparing treatment modalities for epithelial ovarian carcinoma (EOC) patients. We used three clinical databases that contained exhaustive datasets of patients in first-line treatment for EOC in 2012 in three regions of France (n=355). Hospital volume activity was instrumented by the distance from patients’ homes to their hospital, and the population density. We used complete tumor resection as a quality indicator. We found that higher volume hospitals appear to more often make the right decisions in regard to how to treat patients, which contributes to the positive impact of hospital volume activities on patient outcomes. Based on our parameter estimates, we found that the rate of complete tumor resection would increase by 10% with centralized care, and by 6% if treatment decisions were coordinated by high volume centers compared to the ongoing organization of care. In both scenarios, the use of neoadjuvant chemotherapy would increase by 10%. As volume alone is an imperfect correlate of quality, policy makers need to know what volume is a proxy for in order to devise volume-based policies. Centralized care at high volume hospitals was the scenario that led to the highest average patient outcome. However, several barriers, such as the increase in patient travel distances, have prevented such a reform of the organization of care from being applied. An intermediate solution between centralized and decentralized care could be to make lower volume hospitals benefit from the expertise of higher volume hospitals when making treatment decisions.

The best strategy for RAS wild-type metastatic colorectal cancer patients in first-line treatment: A classic and Bayesian meta-analysis.

At present, there is uncertainty on the best systemic treatment in first-line setting for RAS wild-type (WT) metastatic colorectal cancer (mCRC) patients. Indeed, several chemotherapy and biologics combinations showed an improvement on survival. We performed a systematic review with a pair-wise and bayesan meta-analysis to rank the best strategy for these patients. A systematic literature search through March 2017 was performed to evaluate the association between several treatment combinations and overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicity rate (TR) in RAS WT mCRC patients. Data were extracted from studies and pooled using the random-effect model for pair-wise meta-analyses and bayesan model for network meta-analysis (NMA). Eight studies with a total of 2518 individuals were included in the meta-analyses. Pooled analyses for subgroups stratified by type of schedule and tumor location demonstrated that anti-EGFR + doublet had the best OS when compared to doublet ± bevacizumab (0.767; 95%CI, 0.695-0.846; P < 0.0001). This benefit is limited to LSCC when compared to a doublet-based schedule and doublet + bevacizumab (HRs, 0.692; 95%CI, 0.596-0.804; P < 0.001; 0.706; 95%CI, 0.584-0.854; P < 0.001; respectively). No significant differences are detected in PFS, whereas the cetuximab-based regimens showed the highest ORR and TR. In NMA our ranking showed the best performance for FOLFOX + panitumumab. Our study indicates that FOLFOX + panitumumab has the major probability to provide an improvement of survival with a good safety profile in patients with RAS WT mCRC with an added value from selection based on sidedness.

Epidemiology and Clinical Features of Adults Myelodysplastic Syndromes in Algeria: A Population-Based Study. Review of the Algerian Myelodysplastic Syndromes Study Group

BACKGROUND: In Algeria, the incidence of hematologic malignancies has been difficult to estimate for many years and MDS incidence is unclear because of historical lack of population-based registration and possibly because of under diagnosis. Today, many hematological centers, including 17 university hospitals, have been developed in the entire north and have useful epidemiological data pertinent to MDS. We studied the incidence of MDS and its subtypes, age distribution, geographic distribution and trends in the rate of diagnosis over the last 5 years in Algeria.DESIGN AND SETTING: Retrospective analysis of nationwide survey of all adult cases of MDS (>16 years) diagnosed between January 2010 and 31 December 2014.PATIENTS AND METHODS: Patients diagnosed with MDS and referred to all departments of hematology at the 17 participating centers between 2010-2014 were identified. Complete demographic and clinical data, laboratory results, treatment modalities were collected and analyzed.RESULTS: Between 2010 and 2014, a total of 243 patients with newly diagnosed MDS have been identified. The sex ratio (M/F) is: 1:08, and the median age is 64.3 years (16 - 82 years). Globally, 27% of MDS are diagnosed in the whole Western region of the country, 56% in the Centre, 14% in the East and 3% in the south. The crude mean annual incidence rate of MDS was 0.07 per 100,000 inhabitants aged ≥15 years old. 11.2% patients were less than 45 years and 42% were older than 70 years.4.3% patients were from rural areas and 6, 2 % were cigarette smokers.Mean hemoglobin level was 7.8 g/dl, mean WBC level was 6134/µl, mean platelets level was 134907/µl, mean VGM level was 92.7 fl and mean ferretin level was 739.31 ng/ml. The mean blood transfusion units were 13.5 units. 36.3% patients had RCMD, 15.9% had RAEB2 and 13.2% had RAEB1. 34.4% patients had cytogenetic abnormalities, and del-5q was more commonly encountered in 22.7%. The IPSS-R was very low in 18.3%, low in 18.3%, intermediate in 11.8%, high in 7.5% and non-specified in 36.6%. Treatment regimens were supportive care (transfusion RBC with chelation, and platelets) and growth factors (EPO, Romiplostine, and G-CSF). At the date of end point, 44% of patients were alive, 26% were death and 31% were lost of follow up.CONCLUSION: Epidemiologic features of our patients are different from the occidental ones. Mean age of presentation of MDS in Algeria is lower than developed countries. The relatively younger age of patients compared to the Western countries may be due to the demographic composition of our population. The annual incidence is still low, but a continuously increasing incidence rate of MDS has been observed throughout the study period and an overall increase in the number of MDS patients diagnosed nationwide over the last five years indicates a need for additional health care resources including curative and therapy-intense strategies, such as stem cell transplant facilities to optimize outcome. Refractory anemia was the most common subtype in both FAB and WHO classification systems and in both genders. The best supportive care was used in all patients in first line treatment and the Iron overload is a permanent feature of MDS. DisclosuresNo relevant conflicts of interest to declare.

Fludarabine, Cyclophosphamide, and Rituximab in Salvage Therapy of Waldenström's Macroglobulinemia

The combination FCR (fludarabine, cyclophosphamide, and rituximab) proved to be active in Waldenström's macroglobulinemia in a mixed population of untreated and previously treated patients. Prolonged myelosuppression and concerns about purine analogue treatment led to the conclusion that this regimen should be avoided in younger patients in first-line treatment. In this retrospective study on 40 patients we observed a response rate of 80% (32) after FCR salvage treatment with 32.5% (13) of patients reaching at least a very good partial remission. None of the prognostic variables had a significant effect on response or good quality of response achievement. Median event-free survival was reached at 77 months; median progression-free survival was not reached after a median follow-up of 51 months with any difference when categorizing patients according to quality of response. The results of this study suggest that the FCR regimen might overcome poor prognostic features and should be taken into account as salvage treatment. Tardive immunosuppression and myelosuppression warrant accurate patient follow-up.