Two-sided Log-rank Test Research Articles

Addition of High-Dose Cytarabine to Immunochemotherapy before Autologous Stem-Cell Transplantation in Patients Aged 65 Years or Younger with Mantle Cell Lymphoma (MCL Younger): A Long-Term Follow-up of the Randomized, Open-Label, Phase 3 Trial of the European Mantle Cell Lymphoma Network

Addition of High-Dose Cytarabine to Immunochemotherapy before Autologous Stem-Cell Transplantation in Patients Aged 65 Years or Younger with Mantle Cell Lymphoma (MCL Younger): A Long-Term Follow-up of the Randomized, Open-Label, Phase 3 Trial of the European Mantle Cell Lymphoma Network

A Novel Classification of Glioma Subgroup, Which Is Highly Correlated With the Clinical Characteristics and Tumor Tissue Characteristics, Based on the Expression Levels of Gβ and Gγ Genes.

PurposeGlioma is a classical type of primary brain tumors that is most common seen in adults, and its high heterogeneity used to be a reference standard for subgroup classification. Glioma has been diagnosed based on histopathology, grade, and molecular markers including IDH mutation, chromosome 1p/19q loss, and H3K27M mutation. This subgroup classification cannot fully meet the current needs of clinicians and researchers. We, therefore, present a new subgroup classification for glioma based on the expression levels of Gβ and Gγ genes to complement studies on glioma and Gβγ subunits, and to support clinicians to assess a patient’s tumor status.MethodsGlioma samples retrieved from the CGGA database and the TCGA database. We clustered the gliomas into different groups by using expression values of Gβ and Gγ genes extracted from RNA sequencing data. The Kaplan–Meier method with a two-sided log-rank test was adopted to compare the OS of the patients between GNB2 group and non-GNB2 group. Univariate Cox regression analysis was referred to in order to investigate the prognostic role of each Gβ and Gγ genes. KEGG and ssGSEA analysis were applied to identify highly activated pathways. The “estimate” package, “GSVA” package, and the online analytical tools CIBERSORTx were employed to evaluate immune cell infiltration in glioma samples.ResultsThree subgroups were identified. Each subgroup had its own specific pathway activation pattern and other biological characteristics. High M2 cell infiltration was observed in the GNB2 subgroup. Different subgroups displayed different sensitivities to chemotherapeutics. GNB2 subgroup predicted poor survival in patients with gliomas, especially in patients with LGG with mutation IDH and non-codeleted 1p19q.ConclusionThe subgroup classification we proposed has great application value. It can be used to select chemotherapeutic drugs and the prognosis of patients with target gliomas. The unique relationships between subgroups and tumor-related pathways are worthy of further investigation to identify therapeutic Gβγ heterodimer targets.

Abstract OT-36-01: Phase III study of GDC-0077 or placebo (pbo) with palbociclib (P) + fulvestrant (F) in patients with PIK3CA-mutant/hormone receptor-positive/HER2-negative locally advanced or metastatic breast cancer (HR+/HER2- LA/MBC)

Abstract Background HR+/HER2- BC is the most common BC subtype, and adjuvant endocrine therapies (ET) are an integral part of its management; however, ~30% of patients still relapse. Development of ET resistance remains a challenge in HR+/HER2- BC; aberrant phosphoinositide 3-kinase (PI3K) signaling contributes to ET resistance and PIK3CA mutations occur in ~40% of HR+/HER2- BCs. Current research has led to the development of new targeted therapies, including CDK4/6 inhibitors and PI3K inhibitors (alpelisib). Preclinical models have demonstrated synergy between CDK4/6 inhibitors and PI3K inhibitors, with PI3K inhibitors blocking CDK4/6 inhibitor resistance development. GDC-0077 is a potent, selective PI3Kα inhibitor and a mutant p110α-degrader with anti-tumor activity alone and in combination with ET + P in PIK3CA-mutant preclinical models. An ongoing phase I trial showed that GDC-0077 + P + F could be combined at maximum doses. INAVO120 is a phase III, randomized, double-blind, pbo-controlled study that will assess efficacy and safety of GDC-0077/pbo + P + F in patients with PIK3CA-mutant/HR+/HER2- LA/MBC (NCT04191499). Trial design Patients are randomized 1:1 to GDC-0077 (9 mg orally; once daily [QD] continuously on a 28-day cycle) + P (125 mg orally; QD, days 1-21 of each 28-day cycle) + F (500 mg intramuscularly every 28 days with a loading dose in Cycle 1) or pbo + P + F. Circulating tumor DNA or tumor tissue must be positive for a PIK3CA mutation. Eligibility Patients whose disease progressed during/within 12 months of adjuvant ET completion, and who have not received prior systemic therapy for LA/MBC. Aims The primary endpoint is investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints include objective response rate (ORR); best overall response (BoR); duration of response (DoR); clinical benefit rate (CBR); overall survival (OS); safety; patient-reported outcomes; and pharmacokinetics. Statistical methods Patients are stratified by visceral disease, primary vs secondary resistance, and geographic region. For the primary PFS analysis, the treatment arms will be compared using a two-sided stratified log-rank test. The treatment effect will be quantified via a hazard ratio, computed from a stratified Cox proportional-hazards regression, including a 95% confidence interval. Median PFS will be estimated using Kaplan-Meier methodology. Accrual Target enrollment is 400 patients at ~210 sites globally. The study is open for enrollment and, as of 06/04/2020, eight patients have been enrolled. Contact information For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Originally submitted to the ESMO 2020 Virtual Meeting. Citation Format: Nicolas Turner, Komal Jhaveri, Kevin Kalinsky, Sibylle Loibl, Sherene Loi, Seock-Ah Im, Cristina Saura, Peter Schmid, Jennifer L Schutzman, Thomas J Stout, Guiyuan Lei, Katherine E Hutchinson, Eirini Thanopoulou, Dejan Juric. Phase III study of GDC-0077 or placebo (pbo) with palbociclib (P) + fulvestrant (F) in patients with PIK3CA-mutant/hormone receptor-positive/HER2-negative locally advanced or metastatic breast cancer (HR+/HER2- LA/MBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-36-01.

Postoperative Adjuvant Anastrozole for 10 Rather than 5 Years in Patients with Oestrogen Receptor-Positive Breast Cancer: AERAS, a Randomised Multicentre Open-Label Phase III Trial

Background: Treatment with an aromatase inhibitor for 5 years is the standard treatment for postmenopausal hormone receptor-positive breast cancer. We investigated the effects of extending this treatment to 10 years on the risk of breast cancer recurrence. Methods: This prospective, randomised, multicentre open-label phase III study assessed the effect of extending anastrozole treatment for an additional 5 years in postmenopausal patients with stage I–IIIA hormone receptor-positive breast cancer who were disease-free after treatment with either 5 years of anastrozole alone or 2–3 years of tamoxifen followed by 2–3 years of anastrozole. Patients were allocated randomly (1:1) to continue anastrozole (1 mg/day orally) for an additional 5 years or stop anastrozole, using the central computer at the Comprehensive Support Project for Oncology Research Data Centre. Randomisation was stratified by type of postoperative endocrine therapy, nodal status, prior adjuvant chemotherapy, and facility. The primary endpoint was disease-free survival, including breast cancer recurrence, second primary cancers, and death from any cause. This study is registered with UMIN clinical trials registry, number UMI00818. Findings: We enrolled 1697 patients from 117 facilities between November 2007 and November 2012. Patients were assigned randomly to the continue group (n=849) or the stop group (n=848). Follow-up information was available for 1593 patients (n=787 in the continue group, n=806 in the stop group) as the full analysis set. After a median follow-up of 5·1 years, there were 172 events involving disease recurrence or the occurrence of contralateral breast cancer (75 in the continue group and 97 in the stop group) and 40 deaths (21 in the continue group and 19 in the stop group). The 5-year disease-free survival rates were 91% (95% confidence interval [CI] 89–93) in the continue group and 86% (95% CI 83–88) in the stop group (hazard ratio [HR] for disease-free survival 0·61, 95% CI 0·46–0·82; p<0·0010, two-sided log-rank test). The 5-year overall survival rates were 98% in the continue group and 98% in the stop group (HR 1·13, p=0·7042). The 5-year distant disease-free survival rates were 95% in the continue group and 93% in the stop group (HR 0·68, p=0·0553). Sixty-seven second primary cancers occurred, including 24 in the continue group and 43 in the stop group. Menopausal or bone-related all-grade adverse events were more frequent among patients in the continue group than in the stop group, including higher incidences of hot flashes (111 [14%] vs 81 [10%]), stiff joints (162 [21%] vs 98 [12%]), arthralgia (294 [37%] vs 236 [29%]), and new-onset osteoporosis (370 [47%] vs 355 [44%]). Interpretation: Continuing adjuvant anastrozole for an additional 5 years after 5 years’ initial treatment with anastrozole or tamoxifen is safe and beneficial in postmenopausal patients with hormone receptor-positive breast cancer. Trial Registration: This study is registered with UMIN clinical trials registry, number UMI00818. Funding: The Comprehensive Support Project for Oncology Research of the Public Health Research Foundation Declaration of Interest: None to declare. Ethical Approval: Ethical approval was provided by local ethics committees in each hospital.

Higher Checkpoint Inhibitor Arthritis Disease Activity may be Associated With Cancer Progression: Results From an Observational Registry.

ObjectiveTo describe clinical features associated with cancer outcomes of patients with immune checkpoint inhibitor (ICI)‐associated arthritis.MethodsObservational study of patients with ICI‐arthritis enrolled in a single‐center registry. Arthritis phenotype and activity, medications, and cancer status were recorded at every visit. We used descriptive statistic, and Kaplan‐Meier curves using two‐sided log‐rank test and Cox regression analysis were used to identify factors associated with cancer progression‐free survival (PFS).ResultsForty‐two patients with ICI‐arthritis were followed for a median (interquartile range [IQR]) of 7.4 (1.7, 14.7) months. Fifty‐seven percent were female, 33% had melanoma, and 69% received anti–programmed death ligand 1 monotherapy. Median time from ICI initiation to arthritis onset was 2.8 (0.8, 11.2) months. Sixty‐two percent had a rheumatoid arthritis (RA)‐like small‐joint presentation; 27% of all patients were rheumatoid factor and/or cyclic citrullinated peptide positive. Median (IQR) Clinical Disease Activity Index (CDAI) on presentation was 15 (8, 24); 62% required systemic glucocorticoids, 55% required disease‐modifying antirheumatic drugs (DMARDs), and 69% had ongoing arthritis at 6 months. Arthritis led to ICI discontinuation in five patients. In univariate analysis, baseline CDAI, DMARD use, earlier arthritis onset, and longer duration of follow‐up were associated with shorter PFS. In multivariable Cox regression analysis controlling for DMARD use and time to arthritis onset, CDAI was a significant predictor of cancer progression (hazard ratio 1.09, 95% confidence interval [CI] 1.00‐1.19, P = 0.05)ConclusionICI‐arthritis most commonly presents with an RA‐like phenotype. High disease activity, as measured by CDAI, may portend cancer progression.

“Decision for adjuvant treatment in stage II colon cancer based on circulating tumor DNA:The CIRCULATE-PRODIGE 70 trial”

BackgroundAdjuvant treatment for stage II colon cancer remains debated. Finding a tool to select patients at risk for disease recurrence may help the clinical decision. Circulating tumor DNA (ctDNA) has been reported recently as a potential predictive marker for disease recurrence. We thus aim to test its ability to better select stage II colon cancer patients for adjuvant therapy. MethodsThis national, phase III trial (NCT 2019-000935-15) conducted in more than 100 centers in France, plans to screen around 2640 patients in order to randomize (2:1; minimization method) 198 ctDNA positive patients. Patients aged 18 to 75 years with ECOG performance status ≤1 with R0 surgical resection of a pT3-T4aN0 colon or high rectum adenocarcinoma will be randomized within 63 days after curative-intent surgery, to adjuvant mFOLFOX6 (oxaliplatin 85 mg/m², leucovorin 400 mg/m², and 5-FU bolus 400 mg/m2 then 5FU Continuous infusion 2.4 g/m²) every two weeks for 12 cycles or observation. Patients will be followed for maximum 7 years. A gain of 17.5% in 3-yr disease free survival (DFS) is expected (42.5% in the experimental arm vs. 25% in the control arm; HR:0.62; α, 5% [two-sided log-rank test]; 1-β, 80%). Secondary endpoints include 2-yr DFS, overall survival, and toxicity.Recruitement began End of January 2020.

Maximum tumor dimension and tumor volume as prognostic factors in patients with newly diagnosed localized Ewing sarcoma (ES)- a report from the Children’s Oncology Group (COG).

11529 Background: Maximum tumor dimension &gt; 8 cm. and large tumor volume have been reported to be adverse prognostic factors in patients with ES but have not been prospectively evaluated in the context of a phase 3 clinical trial with interval compressed chemotherapy. Methods: COG AEWS1031 (NCT01231906) was a randomized phase 3 clinical trial comparing interval compressed chemotherapy regimens in patients with newly diagnosed localized ES of bone and soft tissue. A correlative objective of AEWS1031 was to evaluate tumor size and volume as prognostic factors. Institution-reported dimensions of the primary tumor from baseline imaging were prospectively collected. For inclusion in this analysis, patients had to have at least 1 tumor dimension reported for tumor size analyses and dimensions in 3 axes for tumor volume analyses. Maximum dimension was dichotomized as less than vs. &gt; / = 8cm. Tumor volume was dichotomized as less than vs. &gt; / = 200 mL. Event-free (EFS) and overall survival (OS) from enrollment were calculated using Kaplan-Meier methods and compared between groups using a two-sided log-rank test. Hazard ratios (HR) and confidence intervals (CI) were calculated using the Cox model. Results: The 5-year EFS and OS of the 629 eligible patients was 78% (95% CI: 75-81%) and 87% (95% CI: 84-90%) respectively and there was no significant difference in both EFS and OS between the randomized interval compressed chemotherapy arms of AEWS1031. 590 of 629 (94%) patients were evaluable for maximum tumor dimension and 307 (52%) had tumors &gt; / = 8 cm. Patients with tumors &gt; / = 8 cm were at significantly increased risk for EFS events (p = 0.016) with estimated 5-year EFS of 73.7% (95% CI: 68.1 vs.78.4%) vs. 82.9% (95% CI 77.7-87.1%) for patients with tumors &lt; 8 cm [HR: 1.53 (1.08-2.17)]. For tumor volume, 586 of 629 patients (93%) were evaluable and 180 (31%) had tumors &gt; / = 200 mL. Patients with tumor volume &gt; / = 200 mL were at significantly increased risk for EFS events (p = 0.003) with estimated 5-year EFS of 70% (95% CI: 62.3-76.4%) vs. 81.6% (95% CI: 77.2-85.2%) for patients with tumors &lt; 200 mL [HR: 1.69 (1.2-2.39)]. Conclusions: Maximum tumor dimension and tumor volume as defined are both prognostic in patients with newly diagnosed localized ES treated with interval compressed chemotherapy. Clinical trial information: NCT01231906 .

Abstract GS3-02: Durvalumab compared to maintenance chemotherapy in patients with metastatic breast cancer: Results from phase II randomized trial SAFIR02-IMMUNO

Abstract Background : While treatment with anti-PDL1 improves outcome in combination with chemotherapy in patients with metastatic triple negative breast cancer, its efficacy is not explored yet in the context of maintenance therapy after chemotherapy, in a population of Her2-negative metastatic breast cancer. Methods : In SAFIR02 trial (NCT : 02299999), patients are selected to present a Her2-negative metastatic breast cancer eligible to 1st or 2nd line chemotherapy. All patients underwent a biopsy of metastatic disease, followed by targeted sequencing and Oncoscan when &amp;gt;30% cancer cells are present on HES slides. After 6 to 8 cycles of induction chemotherapy, patients who present an actionable genomic alteration are randomized between targeted therapies and continuation of maintenance chemotherapy, and patients without actionable alterations are randomized between durvalumab (dose, schedule) for 2 years and maintenance chemotherapy. As a substudy of the SAFIR02-breast trial, the SAFIR02-IMMUNO trial has its primary endpoint, the PFS, hierarchized as the primary end-point of the core of the study. The plan was to include 190 patients in order to have 80% power using a two-sided logrank test at the 5 % level of significance to detect an improvement from 3 months to 4.76 months corresponding to an HR of 0.63. Results : 191 patients have been randomized between durvalumab and maintenance chemotherapy (190 women) until now, 45.5% TNBC and 53.4% RH+. The median age was 55 years. . 91.6% (175/191) patients were randomized on their first line of chemotherapy in metastatic setting. Median number of metastatic sites at the beginning of the chemotherapy line was 2. PDL1 staining was performed on 89 available tumor FFPE blocks using SP142 antibody. 30% (n=27/89) patients presented a PDL1 positive tumor. PFS and OS will be presented at the conference.Conclusion : This is the first randomized trial comparing aPDL1 inhibitor to chemotherapy in the maintenance setting and to address the question of the efficacy of aPDL1i in HR+/Her2- and triple negative breast cancers. Citation Format: Florence Dalenc, Ingrid Garberis, Thomas Filleron, Amélie Lusque, Thomas Bachelot, Monica Arnedos, Mario Campone, Marie-Paule Sablin, Hervé Bonnefoi, Marta Jimenez, Jacquet Alexandra, Fabrice Andre. Durvalumab compared to maintenance chemotherapy in patients with metastatic breast cancer: Results from phase II randomized trial SAFIR02-IMMUNO [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS3-02.

A multicenter randomized placebo controlled trial of rifampin to reduce pedal amputations for osteomyelitis in veterans with diabetes (VA INTREPID)

BackgroundThe prevalence of diabetes mellitus continues to inexorably rise in the United States and throughout the world. Lower limb amputations are a devastating comorbid complication of diabetes mellitus. Osteomyelitis increases the risk of amputation fourfold and commonly presages death.Antimicrobial therapy for diabetic foot osteomyelitis (DFO) varies greatly, indicating that high quality data are needed to inform clinical decision making. Several small trials have indicated that the addition of rifampin to backbone antimicrobial regimens for osteomyelitis outside the setting of the diabetic foot results in 28 to 42% higher cure rates.Methods/designThis is a prospective, randomized, double-blind investigation of the addition of 6 weeks of rifampin, 600 mg daily, vs. matched placebo (riboflavin) to standard-of-care, backbone antimicrobial therapy for DFO. The study population are patients enrolled in Veteran Health Administration (VHA), ages ≥18 and ≤ 89 years with diabetes mellitus and definite or probable osteomyelitis of the foot for whom an extended course of oral or intravenous antibiotics is planned. The primary endpoint is amputation-free survival. The primary hypothesis is that using rifampin as adjunctive therapy will lower the hazard rate compared with the group that does not use rifampin as adjunctive therapy. The primary hypothesis will be tested by means of a two-sided log-rank test with a 5% significance level. The test has 90% power to detect a hazard ratio of 0.67 or lower with a total of 880 study participants followed on average for 1.8 years.DiscussionVA INTREPID will test if a rifampin-adjunctive antibiotic regimen increases amputation-free survival in patients seeking care in the VHA with DFO. A positive finding and its adoption by clinicians would reduce lower extremity amputations and their associated physical and emotional impact and reduce mortality for Veterans and for the general population with diabetic foot osteomyelitis. Given that rifampin-adjunctive regimens are currently employed for therapy for the majority of DFO cases in Europe, and only in a small minority of cases in the United States, the trial results will impact therapeutic decisions, even if the null hypothesis is not rejected.Trial registrationRegistered January 6, 2017 at ClinicalTrials.gov, NCT03012529.

The prognostic value of B7-H6 in esophageal squamous cell carcinoma

B7-H6, a member of the B7 family molecules, participates in the clearance of tumor cells by binding to NKp30 on NK cells. B7-H6 expression level in esophageal squamous cell carcinoma (ESCC) and the clinical value remain unknown. The goal of this study was to determine the expression of B7-H6 in ESCC and further explore its clinical significance. We retrospectively collected the clinical data of 145 patients diagnosed with ESCC between January 2007 and December 2008. The expression of B7-H6 of the pathological tissue samples was detected by immunohistochemistry. The chi-square (χ2) test was used to analyse the relationships of B7-H6 and clinicopathological characteristics. Survival and hazard functions were estimated using the Kaplan-Meier method, and survival between groups was compared using the two-sided log-rank test. The Cox proportional hazards regression model was used to adjust for the risk factors related to overall survival (OS). 133/145 (91.72%) of the ESCC tissue samples exhibited B7-H6 expression. The expression level of B7-H6 was correlated with T stage (P = 0.036) and lymphatic metastasis status (P = 0.044). High B7-H6 expression (P = 0.003) was associated with a significantly worse OS than low B7-H6 expression. Multivariate Cox proportional hazards regression analysis demonstrated that tumour size (P = 0.021), B7-H6 expression (P = 0.025) and lymphatic metastasis status (P = 0.049) were independent prognostic factors of OS for ESCC. Collectively, our findings suggest that B7-H6 is widely expressed in ESCC samples. And B7-H6 may represent a predictor of poor prognosis for ESCC.

ACTR-38. A SINGLE CENTER STUDY: LONG-TERM OUTCOMES OF COMBINED CHEMORADIATION THERAPY WITH TEMOZOLOMIDE FOR NEWLY DIAGNOSED GLIOBLASTOMA IN KOREAN PATIENT

Abstract In newly diagnosed glioblastoma (GBM), Temozolomide (TMZ) during and after radiation therapy has become standard treatment. This study describes the long-term use and follow-up results of this therapy for GBM. From 2004 to 2013 in a single institute, 112 Korean patients with newly diagnosed GBM were analyzed retrospectively. The Kaplan-Meier method, the two-sided log-rank test and Cox’s regression analysis was used to determine survival and its affecting factors. The toxicities of TMZ were evaluated using CTCAE v5.0. During the median follow-up period of 18.8 months, median PFS and OS were 9.2 and 20.3 months, respectively. This better survival outcome than the Stupp’s original study might be probably a large treatment effect of a single institution, ethnicity, and associated genetic factors. The TMZ during radiation therapy was completed in 108 patients (96.4%) and TMZ after radiation therapy in 59 patients (52.7%). Eight patients presented with grade 3 or 4 hematologic toxic effects during the protocol. Sixty-six patients (58.9%) received salvage treatment because of the poor response to adjuvant treatment or progression of the disease who achieved completion of adjuvant treatment was shown significantly longer median OS (p= 0.007) and PFS (p&lt; 0.001). Age (&lt; 60 years), preoperative KPS score (≥ 90), the extent of resection (≥ 78% by volumetric measurement, gross total resection), and completion of the Stupp’s protocol were significant factors affecting better survival. Between the sexes, and ages over 65 years did not show any significant difference among their groups. With marginal significances, the mutated IDH-1 and the methylated MGMT promoter showed longer median PFS(p= 0.075 and 0.777, respectively) and OS (p= 0.085 and 0.131, respectively). TMZ during and after radiation therapy might be effective and safe for newly diagnosed Korean patients with GBM. Further studies about various clinical and genetic factors affecting better survival are mandatory.

The necessity of IIb dissection in T1\u2013T2N0M0 oral squamous cell carcinoma: protocol for a randomized controlled trial

BackgroundThere is a growing debate on the relationship between health-related quality of life (HRQoL) and patient survival which has been going on for the last few decades. The greatest wish of clinicians is to extend the latter while improving the former. Following neck dissection of early-stage oral carcinoma, “shoulder syndrome” appears due to traction of the accessory nerve during removal of level IIb, which greatly affects patient quality of life. Since occult metastasis in level IIb of early-stage oral carcinoma is extremely low, some surgeons suggest that level IIb can be exempt from dissection to improve the HRQoL. However, other surgeons take the opposite view, and thus there is no consensus on the necessity of IIb dissection in T1–2N0M0 oral squamous cell carcinoma (OSCC).MethodsWe designed a parallel-group, randomized, non-inferiority trial that is supported by Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China. We will enroll 522 patients with early oral carcinoma who match the inclusion criteria, and compare differences in 3-year overall survival, progression–free survival (PFS) and HRQoL under different interventions (retention or dissection of level IIb). The primary endpoints will be tested by means of two-sided log-rank tests. Analysis of overall and progression-free survival will be performed in subgroups that were defined according to stratification factors with the use of univariate Cox analysis. In addition, we will use post-hoc subgroup analyses on the basis of histological factors that were known to have effects on survival, such as death of invasion of the primary tumor. To evaluate HRQoL, we will choose the Constant–Murley scale to measure shoulder function.DiscussionCurrently, there are no randomized controlled trials with large sample sizes on the necessity of IIB dissection in T1–T2N0M0 OSCC. We designed this noninferiority RCT that combines survival rate and HRQoL to assess the feasibility of IIb neck dissection. The result of this trial may guide clinical practice and change the criteria of how early-stage oral cancer is managed. The balance between survival and HRQoL in this trial is based on early-stage breast cancer treatment and may provide new ideas for other malignancies.Trial registrationChinese Clinical Trial Registry, ChiCTR1800019128. Registered on 26 October 2018.

P2.01-20 Anlotinib vs. Docetaxel in Advanced Non-Squamous NSCLC (EGFR Wild-Type) After Progression on Platinum-Based Chemotherapy: A Trial Protocol

Anlotinib, an oral VEGFR, FGFR, PDGFR and c-Kit tyrosine kinase inhibitor, showed significantly longer overall survival in a phase 3 trial. In the multi-center, open-label, randomized controlled ALTER-L023 trial, we compared anlotinib with docetaxel as second-line treatment in patients with advanced non-squamous EGFR wild-type non-small cell lung cancer (NSCLC) previously given platinum-based doublet chemotherapy. This multi-center, open-label, randomized controlled ALTER-L023 trial was conducted at 10 hospitals in China. Eligible patients with previously treated non-squamous EGFR wild-type NSCLC were randomly assigned (1:1) to receive anlotinib (12 mg QD from day 1 to 14 of a 21-day cycle) or docetaxel (75mg/m2, on day 1 of a 21-day cycle) till progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS), that was defined as the time from randomization to disease progression or death. The secondary endpoints included objective response rate, disease control rate, duration of response and safety. Based on a two-sided log-rank test at 5% significance level, a power of 80% and a median PFS of 6 months for anlotinib versus 3 months for docetaxel, the simple size was estimated at 77 patients. Allowing for 15% dropouts, the sample size was set at 88 patients (44 patients in both groups). Clinical trial information: NCT03703596 Section not applicable Section not applicable

387TiP - Palbociclib rechallenge in hormone receptor (HR)[+]/HER2[-] advanced breast cancer (ABC). PALMIRA trial

BackgroundThe combination of a CDK4/6 inhibitor (CDK4/6i) with letrozole (LET) or fulvestrant (FUL) is the most active first–line (1L) treatment for patients (pts) with HR[+]/HER2[-] ABC. Although endocrine sensitivity persists beyond progression, preliminary findings suggest more adaptive resistance mechanisms to endocrine therapy (ET) than to CDK4/6i. At present, there are no data about prolonging CDK4/6 blockade beyond progression on a CDK4/6i. The aim of this study is to determine whether palbociclib rechallenge combined with second–line ET upon progression to a prior palbociclib–based therapy will improve progression–free survival (PFS) over ET alone in HR[+]/HER2[-] ABC pts. Trial designThis is an international, open–label, randomized phase II trial. A total of 198 pts will be randomized (2:1) to palbociclib plus ET (LET or FUL) or ET alone, until progressive disease (PD) or unacceptable toxicity. Pts will be stratified by 1L ET and presence of visceral metastasis. Main selection criteria include: (1) Pre– and post–menopausal women with HR[+]/HER2[-] ABC; (2) Evidence of PD on a 1L combination of palbociclib plus LET or FUL after obtaining clinical benefit (secondary resistance); (3) Pts relapsing on or within the first year of a palbociclib–based adjuvant regimen; (4) Measurable and biopsable disease or non–measurable disease with bone lesion. The primary objective is to assess PFS of palbociclib plus ET versus ET alone. The 1st co-primary endpoint is the PFS in the combination arm only. If this objective is achieved, we will compare PFS between the two arms (2nd co-primary endpoint). With 128 events, the 1st and 2nd analyses have an 80% power to detect a 1.4–month (hazard ratio [HR]=0.74) or 2.74–month (HR=0.6) increase over 4–month median PFS for ET arm, respectively. The nominal alpha level is 5% for two-sided log-rank tests. Secondary objectives evaluate: Safety–related outcomes, objective response rate, 6–month clinical benefit rate, overall survival, quality of life, and time to first chemotherapy. Exploratory objectives include: Correlation between the intrinsic molecular subtypes and efficacy/safety findings, and identification of new predictive markers. Clinical trial identificationNCT03809988. First Posted: January 18, 2019. Legal entity responsible for the studyMedica Scientia Innovation Research (MedSIR). FundingPfizer S.L.U. DisclosureA. Llombart Cussac: Honoraria (institution), Advisory / Consultancy: Roche, GlaxoSmithKline, Novartis, Celgene, Eisai, AstraZeneca; Research grant / Funding (institution): GlaxoSmithKline, Sanofi, Puma Biotechnology; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Medica Scientia Innovation Research (MedSIR). P. Schmid: Advisory / Consultancy: Pfizer, AstraZeneca, Novartis, Merck, Boehringer Ingelheim, Bayer, Eisai, Celgene, Puma; Research grant / Funding (institution): AstraZeneca, Genentech, Roche, Oncogenex, Novartis, Astellas; Spouse / Financial dependant, Spouse is consulting for Genentech/Roche: Genentech/Roche. I. Macpherson: Honoraria (self): Celldex, Daiichi Sankyo, Eisai, Genomic Health, Novartis, Pfizer, Roche; Travel / Accommodation / Expenses: Eisai, Roche. J. Gligorov: Advisory / Consultancy: Daïchi, EISAI, Genomic Health, Ipsen, Macrogenics, MSD, Novartis, Onxeo, Pfizer, Roche Genentech; Travel / Accommodation / Expenses: EISAI, Genomic Health, MSD, Novartis, Pfizer, Roche Genentech; Non-remunerated activity/ies: Daichi, EISAI, Genomic Health, Immunomedics, Novartis, Pfizer, Roche Genentech. M. Sampayo: Full / Part-time employment: Medica Scientia Innovation Research (MedSIR). F. Riva: Full / Part-time employment: Medica Scientia Innovation Research (MedSIR). A. Malfettone: Full / Part-time employment: Medica Scientia Innovation Research (MedSIR). J.M. Pérez-García: Advisory / Consultancy: Roche, Lilly; Full / Part-time employment: Medica Scientia Innovation Research (MedSIR). J. Cortés: Advisory / Consultancy: Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex; Honoraria (institution): Roche, Novartis, Celgene, Eisai, Pfizer, Samsung; Research grant / Funding (institution): Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Medica Scientia Innovation Research (MedSIR). All other authors have declared no conflicts of interest.

EGFR-TKIs plus bevacizumab demonstrated survival benefit than EGFR-TKIs alone in patients with EGFR-mutant NSCLC and multiple brain metastases

IntroductionPrevious studies suggested that epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKIs) plus bevacizumab could significantly prolong progression-free survival (PFS) than EGFR-TKI alone as first-line setting for patients with EGFR-mutant non-small-cell lung cancer (NSCLC). However, whether this combination could benefit patients with multiple brain metastases (BrMs) remains undetermined. MethodsA total of 208 patients with EGFR-mutant NSCLC and multiple BrM (number >3, at least one of lesions was measurable) were retrospectively identified. Kaplan-Meier curves with two-sided log-rank tests and Cox proportional hazards model with calculated hazard ratios and 95% confidence intervals were used to determine the survival difference. ResultsOf all patients, 149 patients received EGFR-TKIs monotherapy and 59 received EGFR-TKIs plus bevacizumab as first-line setting. EGFR-TKIs plus bevacizumab was associated with a significantly higher intracranial objective response rate (ORR, 66.1% vs. 41.6%, P = 0.001), systemic ORR (74.6% vs. 57.1%, P = 0.019), longer intracranial PFS (14.0 vs. 8.2 months; P < 0.001) and systemic PFS (14.4 vs. 9.0 months; P < 0.001). Importantly, addition of bevacizumab also had a significantly longer overall survival (OS, 29.6 vs. 21.7 months; P < 0.001). Multivariate analysis consistently revealed that addition of bevacizumab was independently associated with prolonged intracranial and systemic PFS, and OS. No unexpected serious adverse effects were observed. ConclusionsEGFR-TKIs plus bevacizumab prolonged not only PFS but also OS in patients with EGFR-mutant NSCLC and multiple BrMs when compared with EGFR-TKIs alone, indicating that this combination could be an alternative therapeutic option for those patients.

PIK3CA mutation as a prognostic factor in HPV-associated oropharynx cancer.

6011 Background: PIK3CA is the most frequently mutated gene in HPV-associated oropharyngeal SCC (OPSCC), with a prevalence of 20-30%. While PIK3CA mutations have been associated with adverse outcomes in cervical cancer, their prognostic significance in HPV-associated OPSCC remains unknown. We sought to elucidate the significance of PIK3CA mutations in a prospective cohort of HPV-associated OPSCC patients treated with definitive chemoradiation (CRT). Methods: Seventy-eight patients with HPV-associated OPSCC were prospectively enrolled on three protocols: LCCC 1121 (NCT03161821) or two phase II clinical trials of de-intensified CRT (NCT02281955 / NCT03077243). De-intensified regimen was 60 Gy IMRT with concurrent cisplatin (30mg/m2). Next-generation sequencing of tumor samples was performed using a targeted panel-based assay (UNCSeq), including over 200 genes. We estimated disease-free survival (DFS) using the Kaplan-Meier method and compared treatment groups with two-sided log-rank test (Medcalc). Results: Sequencing was performed in 78 patients with a median follow-up of 24 months. Seventy-five patients received 60Gy; three patients received 70Gy. Ten patients had disease recurrence (2 regional only, 5 distant only, 3 regional and distant). Thirty-eight of 78 patients had at least one mutation identified (17 PIK3CA, 4 PTEN, 3 KRAS, 3 FBXW7, 3 FGFR3, 2 TP53, 2 prothrombin 20210, 1 NRAS, 1 BRCA1, 1 factor V Leiden, 1 FLT3, 1 RAD50, 1 PIK3R1). The most common site of PIK3CA mutation was the helical domain (E545K – 8/17, E542K – 2/17). Despite similar T/N staging and tobacco pack years, patients with WT-PIK3CA had significantly higher DFS (93%) compared with 65% for patients with PIK3CA mutations (p = 0.0009). Patients with mutations other than PIK3CA also had improved DFS relative to those with PIK3CA mutations (96% vs. 65%; p = 0.0147). Conclusions: PIK3CA mutation is associated with worse DFS in a prospective cohort of newly diagnosed HPV-associated OPSCC patients treated with definitive CRT. These findings suggest that patients with PIK3CA mutations may not be suitable for de-intensified therapy and investigation of novel treatment strategies may be appropriate.

Overall Survival with Fulvestrant plus Anastrozole in Metastatic Breast Cancer

BackgroundWe previously reported prolonged progression-free survival and marginally prolonged overall survival among postmenopausal patients with hormone receptor–positive metastatic breast cancer who had been randomly assigned to receive the aromatase inhibitor anastrozole plus the selective estrogen-receptor down-regulator fulvestrant, as compared with anastrozole alone, as first-line therapy. We now report final survival outcomes.MethodsWe randomly assigned patients to receive either anastrozole or fulvestrant plus anastrozole. Randomization was stratified according to adjuvant tamoxifen use. Analysis of survival was performed by means of two-sided stratified log-rank tests and Cox regression. Efficacy and safety were compared between the two groups, both overall and in subgroups.ResultsOf 707 patients who had undergone randomization, 694 had data available for analysis. The combination-therapy group had 247 deaths among 349 women (71%) and a median overall survival of 49.8 months, as compared with 261 deaths among 345 women (76%) and a median overall survival of 42.0 months in the anastrozole-alone group, a significant difference (hazard ratio for death, 0.82; 95% confidence interval [CI], 0.69 to 0.98; P=0.03 by the log-rank test). In a subgroup analysis of the two strata, overall survival among women who had not received tamoxifen previously was longer with the combination therapy than with anastrozole alone (median, 52.2 months and 40.3 months, respectively; hazard ratio, 0.73; 95% CI, 0.58 to 0.92); among women who had received tamoxifen previously, overall survival was similar in the two groups (median, 48.2 months and 43.5 months, respectively; hazard ratio, 0.97; 95% CI, 0.74 to 1.27) (P=0.09 for interaction). The incidence of long-term toxic effects of grade 3 to 5 was similar in the two groups. Approximately 45% of the patients in the anastrozole-alone group crossed over to receive fulvestrant.ConclusionsThe addition of fulvestrant to anastrozole was associated with increased long-term survival as compared with anastrozole alone, despite substantial crossover to fulvestrant after progression during therapy with anastrozole alone. The results suggest that the benefit was particularly notable in patients without previous exposure to adjuvant endocrine therapy. (Funded by the National Cancer Institute and AstraZeneca; ClinicalTrials.gov number, NCT00075764.)

Abstract P2-08-58: Prognostic factors of survival in node positive breast cancer patients after neoadjuvant chemotherapy in a large series after 5y follow-up: Can response overcome the poor prognosis of nodal stage?

Abstract Background: Status of the axilla is one of the most significant prognostic factors in breast cancer (BC) patients. On the other hand, response to neoadjuvant chemotherapy (NACT) is related to survival. The aim of the present study is to analyze which prognostic factors impact most on Node positive (N+) BC patient survival after NATC. Material and methods: Retrospective analyses on a series of N+ BC patients treated with NATC based on anthracyclines and taxanes +/- trastuzumab if HER2 positive tumors, between June 2008 and December 2016. Clinical, radiological and pathological outcomes have been evaluated. Residual cancer burden (RCB) 1 and the neoadjuvant response index (INR) 2 have been recorded. Survival was calculated with Kaplan-Meier survival curve since the start of NATC to the first documented disease recurrence (DFS) or death (OS). Hazard ratios (HRs) with 95% CIs were estimated with cox proportional hazards regression analysis and subgroups were compared with a two-sided log-rank test. Results: A total of 345 N+ BC patients were included. Pathological complete response was achieved in 72 (20.8%) patients. After NACT, 137 (39.6%) become ypN0, 9 (2.6%) ypN1 mic, 113 (32.7%) ypN1, 60 (17.3%) ypN2 and 26 (7.6%) N3. Those independent predictive factor of ypN0 were molecular subtype (TN and Her2+) with OR: 7.7, p&amp;lt;0.001 and clinical response with OR 6.88, p: 0.04. At a mean follow-up of 58 months there have been 73 (21.1%) recurrences: 9 (2.3%) local, 45 (13%) systemic, 15 (4.3%) systemic+ local, 3 (0.9%) axilla, 1 (0.3%) supraclavicular. The estimated 5y OS was 87.8%. The univariate analysis according to DSF is detailed in Table1. Adjusted univariate anaalysis cox regression of clinical and pathological factors of desease free survivalBMI10.989-1.010.963AGE0.9960.953-1.0420.876Dose NATC0.9940.979-1.0080.402Clinical Stage1.4021.077-1.8260.012Rx Image1.260.803-1.9940.311Rx size1.0090.995-1.0240.217Number suspicious ALN1.0950.801-1.4970.57Molecular subtype TN,HER20.8800.534-1.450.616Nottinghan grade1.0460.753-1.4530.789Histological subtype1.4651.044-2.0570.27MOlecular subtype1.1510.956-1.3850.137Vascular invasion1.6761.137-24710.009Clinical response2.3691.709-3.284&amp;lt;0.001Fibrosis tumor bed0.980.972-0.989&amp;lt;0.001Nodal fibrosis&amp;gt;50%1.7950.874-3.6860.111Pathological tumoral response1.6861.175-2.4180.005ypN03.561.853-6.838&amp;lt;0.001NRI0.330.192-0.565&amp;lt;0.001RCB1.2741.106-1.4680.001 In the multivariate model those parameters that were independently prognostic were clinical response HR: 5.44 (IC95% 2.275-13.042, p&amp;lt;0.001) and clinical stage HR: 2.364 (IC95% 1.018-5.490, p: 0.045). Conclusions: The most significant prognostic factor in our N+ series was response to NATC, followed by clinical stage. Those independently predictive factors of axillar response (ypN0) were molecular subtype (TN and Her2+) and clinical response. In conclusion, in those patients with chemo sensitive tumors, lymphadenectomy could be safely spared with a more selective axillary approach. Citation Format: Fernandez S, Garcia A, Vethencourt A, Vazquez S, Petit A, Pla MJ, Ortega R, Pérez J, Gil M, Ponce J, Pernas S, Lopez A, Falo C. Prognostic factors of survival in node positive breast cancer patients after neoadjuvant chemotherapy in a large series after 5y follow-up: Can response overcome the poor prognosis of nodal stage? [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 P2-08-58.

Abstract GS3-04: A prospective randomized multi-center open-label phase III trial of extending aromatase-inhibitor adjuvant therapy to 10 years - Results from 1697 postmenopausal women in the N-SAS BC 05 trial: Arimidex extended adjuvant randomized study (AERAS)

Abstract Background: Treatment with an aromatase inhibitor for 5 years as up-front monotherapy or after tamoxifen therapy for 2-3 years is the treatment of choice for hormone-receptor-positive breast cancer in postmenopausal women. Extending treatment with an aromatase inhibitor to 10 years may reduce the risk of breast cancer recurrence. Methods: We conducted a prospective randomized multi-center open-label phase III trial to assess the effect of the extended use of anastrozole for an additional 5 years. Postmenopausal patients with stageI-III, hormone-receptor-positive breast cancer, disease-free after 5 years of either anastrozole alone or tamoxifen 2-3 years followed by anastrozole 3-2 years were randomized to continual group with anastrozole for an additional 5 years or stop group without an additional anastrozole. Our primary end point was disease-free survival. Results: We enrolled 1697 women. After a median follow up of 4.9 years, there were 149 events involving disease recurrence or the occurrence of contralateral breast cancer (51 in continual group and 98 in stop group) and 7 deaths (3 in continual group and 4 in stop group). The 5-year disease-free survival rate was 91.9% (95% confidence interval [CI], 89.4 to 93.8) in continual group and 84.4% (95% CI: 80.0 to 88.0) in stop group (hazard ratio for disease-free survival,0.548 ;P=0.0004. by a two-sided log-rank test stratified according to nodal status, prior adjuvant chemotherapy, institution, and choice of anastrozole or tamoxifen). The rate of 5-year overall survival was 99.5% in continual group and 99.6% in stop group. (hazard ratio,1.389 ;P=0.665). The rate of 5-year distant disease-free survival was 97.2% in continual group and 94.3% in stop group (hazard ratio,0.514 ;P=0.0077). Bone-related adverse events were observed more frequently among patients in continual group than among patients in stop group, including a higher incidence of bone pain, stiff joints, bone fractures, and new-onset osteoporosis. Conclusion: The extension of treatment with an adjuvant aromatase inhibitor (anastrozole) to 10 years resulted in significantly higher rates of disease-free survival and distant disease-free survival than those with no additional anastrozole, but the rate of overall survival was not different between two groups. Our study shows that it is safe and beneficial for postmenopausal patients with hormone-receptor-positive breast cancer to take an anastrozole as adjuvant therapy for an additional 5 years after initial treatment. (UMIN:000000818) Citation Format: Ohtani S, Iijima K, Higaki K, Sato Y, Hozumi Y, Hasegawa Y, Takei H, Tanaka M, Yagata H, Masuoka H, Tanabe M, Egawa C, Komoike Y, Saji S, Nakamura T, Yanagita Y, Ohtsu H, Mukai H, Iwase T. A prospective randomized multi-center open-label phase III trial of extending aromatase-inhibitor adjuvant therapy to 10 years - Results from 1697 postmenopausal women in the N-SAS BC 05 trial: Arimidex extended adjuvant randomized study (AERAS) [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 GS3-04.

Restrictive Transfusions in the Era of Pathogen-Inactivated Platelets: A Single Center Experience

Introduction Blood management and infectious disease mitigation are essential for success with allogeneic stem cell transplant (alloSCT). We sought to investigate the safety profile of a proactive infection mitigation strategy with the use of pathogen-inactivated (PI) platelets (PLT) during the alloSCT peri-engraftment period in the era of restrictive blood transfusion. Methods We retrospectively analyzed data from patients undergoing alloSCT that received prophylactic red blood cell (RBC) and PLT transfusion triggered by a hemoglobin of 8 g/dL and PLT count of 15,000 PLT/mL. When available, PI PLT (non-irradiated) were used starting November 2016 until March 2018 (study timeframe). Statistical analysis was performed using SAS 9.4 (Cary, NC). Patients characteristics and clinical parameters were summarized using mean and standard deviation or median and range for continuous data, and frequency and percentage for categorical data. Kaplan-Meier analysis was used to estimate progression-free survival (PFS) and overall survival (OS) from day of transplant. A two-sided logrank test was used to compare across strata using p Results Sixty-eight patients received alloSCT. Median age at transplant was 55 years (range [R], 18-73). Peripheral blood stem cells were the graft source in all but one patient. Donor source was a matched related, 10/10 matched unrelated (MUD), 9/10 MUD and haploidentical donor in 30.9%, 44.1%, 2.9%, and 22.1% of cases, respectively. Myeloablative conditioning was used in 45.6% of patients. Indication for alloSCT was a myeloid or lymphoid disorder in 64.7% and 35.3% of cases. Median time to neutrophil and PLT engraftment was 12 (R, 10-35) and 12 days (R, 8-120), respectively. Pre-alloSCT RBC alloimmunization was present in 11.8% of patients. Cumulative incidence of grades II-IV acute and chronic graft-versus-host disease (GVHD) was 20.6% and 22.1%, respectively. PI PLT were used in 73.5 % patients. There were no cases of transfusion associated graft failure (GF) or GVHD. Bacteremia occurred in 10.0% and 22.1% of patients by 30 days and 100 days post-alloSCT, respectively, and were both associated with worse OS (both p Conclusions Restrictive prophylactic transfusion thresholds in alloSCT recipients is feasible. Limited PI PLT transfusion was not associated with transfusion-attributable GVHD, GF or infectious complications. Future prospective studies should determine the short term hemostatic efficacy and long term post-alloSCT outcomes with restrictive transfusion criteria in an era of expanding PI product use.