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Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in

Background: Fibroblast growth factor receptor (FGFR) alterations are promising targets in different tumors. We report results of FIGHT-207, an open-label, single-arm phase 2 study of pemigatinib, a potent, selective FGFR1-3 inhibitor, in patients with previously treated unresectable or metastatic FGFR-altered solid tumors (NCT03822117). Methods: Patients were assigned to cohorts A (FGFR1-3 fusions), B (FGFR1-3 activating non-kinase domain mutations), and C (FGFR1-3 kinase domain mutations and alterations of unknown significance) and received continuous 13.5 mg pemigatinib once daily. Prior FGFR inhibitor treatment was prohibited. The primary endpoint was objective response rate (ORR) per RECIST v1.1 or RANO as confirmed by independent central review. Results: 107 patients were enrolled and assigned to cohorts A (n=49), B (n=32), and C (n=26). ORR in cohorts A, B, and C was 26.5%, 9.4%, and 3.8%, respectively. Responses were observed for multiple tumor types, including gliomas and gynecologic and pancreatic tumors (Table). Notably, we saw responses for several infrequent FGFR alterations, including an FGFR1 kinase domain mutation (K656E) and an FGFR2 extracellular in-frame deletion (FGFR2 I291_Y308Del). Among patients in cohorts A+B with centrally confirmed FGFR alterations, BAP1 co-alterations were observed in 47% (7/15) of responders, and TP53 co-alterations were present in 43% (23/53) of nonresponders. Safety was consistent with prior reports. Conclusions: In addition to cholangiocarcinoma, pemigatinib showed clinical activity in gliomas, gynecologic tumors, and pancreatic cancer and safety was consistent with prior reports. We observed responses in patients with previously unreported FGFR alterations, suggesting that a broader population of patients may benefit from FGFR inhibitors. Further correlative work to predict response to therapy is needed to better identify these patients. Table. Characteristics of Patients With Best Percentage Change From Baseline in Target Lesion Size ≥30% Patient Tumor Type FGFR alteration* BOR Best % Change From BL in Target Lesion Size PFS, mo Gliomas 1 Glioblastoma FGFR3 fusion CR −100.0 20.2† 2 Glioblastoma FGFR3 fusion PR −100.0 8.4† 3 Diffuse astrocytoma FGFR1 K656E mutation PR −80.7 8.0 Gynecologic 4 Cervical cancer FGFR3 fusion PR −100.0 6.4 5 Cervical cancer FGFR3 fusion PR −32.1 6.3 6 Endometrial cancer FGFR1 rearrangement SD −100.0 1.9† 7 Ovarian cancer FGFR2 fusion SD −44.0 2.1† 8 Cervical cancer FGFR2 C382R mutation SD −35.6 5.6 Pancreatic 9 Pancreatic adenocarcinoma FGFR2 fusion PR −72.1 8.4† 10 Pancreatic adenocarcinoma 2 FGFR2 fusions PR −54.9 8.9† 11 Pancreatic adenocarcinoma FGFR2 fusion PR −33.3 6.3† 12 Pancreatic adenocarcinoma FGFR2 fusion SD −100.0 2.7 Cholangiocarcinoma 13 Cholangiocarcinoma FGFR2 fusion PR −64.6 6.2 14 Cholangiocarcinoma FGFR2 fusion PR −61.4 9.9 15 Cholangiocarcinoma FGFR2 fusion PR −53.5 8.8 16 Cholangiocarcinoma FGFR2 C382R mutation PR −49.7 6.0 17 Cholangiocarcinoma FGFR2 fusion PR −46.2 5.9† 18 Cholangiocarcinoma FGFR2 fusion PR −43.2 10.5 19 Cholangiocarcinoma FGFR2 I291, Y308 deletion PR −42.5 14.8 20 Cholangiocarcinoma FGFR2 fusion PR −34.1 11.2† 21 Cholangiocarcinoma FGFR2 fusion SD −42.2 2.5† 22 Cholangiocarcinoma FGFR2 Y375C mutation SD −37.5 3.7† 23 Cholangiocarcinoma FGFR2 W290C mutation SD −34.0 10.5 Urothelial tract/bladder cancer 24 Urothelial tract/bladder cancer FGFR3 Y373C mutation PR −50.8 6.2† 25 Urothelial tract/bladder cancer FGFR3 Y373C mutation SD −30.0 3.9 Other 26 Non-small cell lung cancer FGFR2 fusion SD −72.0 4.1 27 Prostate cancer FGFR2 fusion SD −32.5 6.4 BL, baseline; BOR, best overall response; CR, complete response; FGFR, fibroblast growth factor receptor; PFS, progression-free survival; PR, partial response; SD, stable disease. * Includes FGFR alterations confirmed through both local and central genetic testing reports. † Censored. Citation Format: Jordi Rodon, Silvia Damian, Muhammad Furqan, Jesus Garcia-Donas, Hiroo Imai, Antoine Italiano, Iben Spanggaard, Makoto Ueno, Tomoya Yokota, Luisa Veronese, Natalia Oliveira, Xin Li, Aidan Gilmartin, Lipika Goyal. Clinical and translational findings of pemigatinib in previously treated solid tumors with activating FGFR1-3 alterations in the FIGHT-207 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT016.

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan–Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81–0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36–0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.

Background The Tumor Microenvironment (TME) has a key role in solid tumor therapy screening. We have developed a 3D ex vivo immunosuppressive assay mimicking the TME. It enables both allogenic & autologous tumor lysis by expanded Tumor Infiltrate Lymphocytes (TILs). It is a valuable 3D assay to study the activity of immune therapy drugs in patient sample. Methods TME-aligned immunosuppressor media was produced by conditioned media from activated human Mesenchymal Stem Cells (hMSC). The TILs were expanded from patient-derived tumor samples and used for tumor killing potential evaluation. Target tumor cells were obtained from different sources: a) Isolated from patient-derived material and frozen until use in experiments with autologous or allogenic TILs or b) Tumor cell lines purchased from ATCC. The cells were mixed according to desired Effector:Target (E:T) ratios and embedded in 3D matrix in presence of TME-aligned media and immune therapy compounds, as Immune Checkpoint inhibitors (ImmChPi). The cell retrieval was performed at the end of desired timepoints and tumor cell killing and TILs activation profile were analyzed by flow cytometry. Results The in vitro expanded TILs were able to kill autologous and allogenic tumor cells in several different E:T ratios within 24 hours. The% tumor cell killing for allogenic samples of the same cancer type showed a similar range as autologous killing. In a representative autologous E:T experiment we observed 40% of killing at E:T ratio 10:1 (figure 1A). These same TILs showed even higher% tumor killing against allogenic tumor samples (up to 90%, data not shown). The Immune Check Point (ImmChP) expression during expansion may change and was followed to select proper expansion timelines. For example, in a particular ovarian cancer sample TIM3 was expressed in 75% of the expanded TILs (figure 1B) and the treatment with TIM3 blocking antibody increased nearly 2-fold tumor cell killing in a dose dependent manner (figure 1C). Conclusions The Novel TME-Aligned 3D IO Assay is a reliable, and powerful tool to study the mode of action of tumor cells lysis by expanded TILs. Immune Therapy Drugs Screening can be performed in autologous or allogenic E:T conditions, allowing full mode of action description of Bi or Multispecific antibodies, ImmChPI and others, and opens a new door for therapy prediction studies in patient‘s material. Ethics Approval The study was approved by Hospital 12 de Octubre Ethics Board, with approval number 14/199. Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Aim: To report results from the Spanish subset included in the radium-223 international early access program (iEAP). Patients & methods: Ninety patients with castration-resistant prostate cancer and bone metastases received radium-223 55 kBq/kg every 4 weeks for six cycles. Results: The median time to disease progression was 8 months and to prostate-specific antigen progression was 4 months. The percentage of patients with ≥50% confirmed declines in prostate-specific antigen was 9%. The median overall survival was 14 months. Grade 3 or 4 treatment emergent adverse events (TEAEs) occurred in 34% of patients (serious TEAEs 28%, TEAEs leading to discontinuation 27%). Conclusion: Outcomes of the Spanish subset are consistent with the iEAP. Radium-223 was generally well tolerated with no safety concerns.

BACKGROUND: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial. METHODS: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres) in 14 countries. Eligible patients were aged 18 years or older with biopsy-confirmed International Federation of Gynecology and Obstetrics (FIGO) stage III to IV epithelial ovarian, primary peritoneal, or fallopian tube cancers, and an ECOG performance status of 0 or 1. Eligible patients were randomly assigned (2:1) using a permuted block method (block size of six patients) to receive six cycles of paclitaxel (175 mg/m2) and carboplatin (area under the serum concentration-time curve 5 or 6) every 3 weeks, plus weekly intravenous trebananib 15 mg/kg or placebo. Maintenance therapy with trebananib or placebo continued for up to 18 additional months. The primary endpoint was progression-free survival, as assessed by the investigators, in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01493505, and is complete. FINDINGS: Between Jan 30, 2012, and Feb 25, 2014, 1164 patients were screened and 1015 eligible patients were randomly allocated to treatment (678 to trebananib and 337 to placebo). After a median follow-up of 27·4 months (IQR 17·7-34·2), 626 patients had progression-free survival events (405 [60%] of 678 in the trebananib group and 221 [66%] of 337 in the placebo group). Median progression-free survival did not differ between the trebananib group (15·9 months [15·0-17·6]) and the placebo group (15·0 months [12·6-16·1]) groups (hazard ratio 0·93 [95% CI 0·79-1·09]; p=0·36). 512 (76%) of 675 patients in the trebananib group and 237 (71%) of 336 in the placebo group had grade 3 or worse treatment-emergent adverse events; of which the most common events were neutropenia (trebananib 238 [35%] vs placebo 126 [38%]) anaemia (76 [11%] vs 40 [12%]), and leucopenia (81 [12%] vs 35 [10%]). 269 (40%) patients in the trebananib group and 104 (31%) in the placebo group had serious adverse events. Two fatal adverse events in the trebananib group were considered related to trebananib, paclitaxel, and carboplatin (lung infection and neutropenic colitis); two were considered to be related to paclitaxel and carboplatin (general physical health deterioration and platelet count decreased). No treatment-related fatal adverse events occurred in the placebo group. INTERPRETATION: Trebananib plus carboplatin and paclitaxel did not improve progression-free survival as first-line treatment for advanced ovarian cancer. The combination of trebananib plus carboplatin and paclitaxel did not produce new safety signals. These results show that trebananib in combination with carboplatin and paclitaxel is minimally effective in this patient population. FUNDING: Amgen. ispartof: LANCET ONCOLOGY vol:20 issue:6 pages:862-876 ispartof: location:England status: published

4577 Background: Cancer is recognized as a major risk factor for severe COVID19. However little is known about the impact of oncologic treatments in the evolution of the disease. On the other hand, the influence of SARS-CoV2 in cancer response remains to be established. We aim to determine both aspects in renal cancer patients receiving different therapeutic options. Methods: We designed a retrospective case-control study to compare the outcome of patients with advanced renal cancer who developed COVID19 under antiangiogenic treatment (cohort A [ChA]) vs immunotherapy (alone or in combination: cohort B [ChB]) vs matched controls (cohort C [ChC]). Controls were renal cancer patients who were not infected during the period of study. One control per case was selected regarding age, gender, kidney cancer histology and type of treatment. Results: From May 20 to Feb 21, 80 patients were recruited. We present the first 55 patients included (15 ChA, 16 ChB and 20 ChC, 4 patients were screening failure) from 13 centers in Spain. Median age was 62 (range 25 to 88) overall and 62 (range 44 to 88) in Ch A, 64,5 (range 42 to 83) in ChB and 61 (range 41 to 77) in ChC. 38 patients were male and 13 were female. Overall 45 cases were clear cell carcinoma (13 ChA, 14 ChB and 18 ChC), 4 papillary (1 ChA, 2 ChB and 1 ChC), 1 chromophobe (ChA) and 1 unclassified (ChC). Median number of prior lines of treatment was 2 (range 1 to 6) overall, (1 [range 1 to 4] in ChA, 2 [range 1 to 4] in ChB and 2 [range 1 to 6] in ChC). 25 patients required treatment interruptions (8 in ChA [32%], 14 in ChB [56%] and 3 [12%] in ChC). 9 patients were hospitalized (4 in Ch A, 5 in ChB and none in ChC) for a median of 10 days (range 4 to 16) overall (7 [range 4 to 14] in ChA and 12 [range 5 to 16] in ChB). No patient required ICU admission. Best tumor response was complete or partial (CR+PR) in 25 patients (5 [20%] in ChA, 9 [36%] in ChB and 11 [44%] in ChC). Clinical benefit (CR+PR+stable disease) was observed in 38 patients (11 [28,9%] in ChA, 10 [26,3%] in ChB and 17 [44,7%] in ChC). One patient in ChB died (due to COVID19). Updated results will be presented. Conclusions: Patients with renal cancer who developed COVID19 held treatment more frequently and presented lower clinical benefit rates than non infected cases. Patients receiving immunotherapy required more frequent dose interruptions and longer hospitalizations than cases on antiangiogenics. These results point to an impact of SARS-CoV2 in renal cancer outcome. Therapies administered to treat renal cancer, could play a role in the evolution of COVID19.

[Abstract] Background: A pivotal, randomized, phase III trial demonstrated a statistically significant superiority of sunitinib over interferon-α in metastatic renal cell carcinoma (mRCC) patients. Objective: To evaluate the effectiveness and safety of sunitinib in patients with advanced or mRCC in routine clinical practice. Methods: Retrospective pooled analysis of clinical data from three observational and prospective studies carried out between 2007 and 2011 in 33 Spanish hospitals. Tumor response, Progression-free survival (PFS) and overall survival (OS), and main sunitinib-related toxicities were registered. Results: 224 patients were analyzed. Median PFS 10.6 months (95% CI: 9.02–12.25), median OS 21.9 months (95% CI: 17.2–26.6). Objective response rate (ORR) 43.8% (95% CI: 36.8–50.7). Median time to PR was 3.8 months (95% CI: 3.86–5.99) and to CR 8.2 months (95% CI: 4.75–9.77). The most common ≥ grade-3 AEs were asthenia/fatigue (18.7%), hand-foot syndrome (6.2%), hypertension (5.8%) and neutropenia (4.8%). Hand-foot syndrome, diarrhea and mucositis were confirmed as independent predictors for PFS and/or OS in a multivariate analysis (p < 0.05) Conclusions: Outcomes with sunitinib in daily clinical practice resemble those obtained in clinical trials. Long-term benefit with sunitinib is possible in advanced RCC patients but the appropriate management of toxicities is mandatory to enable patients to remain on treatment.

2538 Background: There is a high unmet medical need for effective treatments for patients with recurrent, metastatic, or persistent cervical cancer. Most patients are young and survival rates are poor. ORR for second line therapies is between 4 and 14% for chemotherapy and recently approved immunotherapy. Adoptive cell transfer using tumor infiltrating lymphocytes (TIL) have demonstrated durable responses in some patients with recurrent cervical cancer thus offering the potential for long-term disease control. Methods: Study C-145-04 is an ongoing, open-label, multicenter Phase 2 clinical trial evaluating the safety and efficacy of LN-145 TIL therapy in patients with advanced cervical cancer who have undergone at least one prior line of chemotherapy. Prior checkpoint inhibitor therapy is an exclusion criterion. The primary endpoint is ORR per RECIST 1.1; secondary endpoints include duration of response (DOR), disease control rate (DCR), and LN-145 safety. Tumors surgically harvested at local institutions are shipped to central GMP facilities for TIL generation in a 22-day manufacturing process. Final LN-145 TIL product is cryopreserved and shipped to sites. Patients receive one week of preconditioning lymphodepletion (cyclophosphamide, fludarabine), a single LN-145 infusion, followed by up to 6 doses of IL-2 (600,000 IU/kg). Results: As of 4 Feb 2019, 27 efficacy-c patients have received Gen 2 of LN-145, with a mean age of 47 years and 2.6 mean prior lines of therapy. Preliminary efficacy results: ORR was 44% (1 CR, 9 PR, 2 uPR), DCR was 89% at 3.5-month median study follow-up with 11/12 patients maintaining their response. Improved responses were observed in 4 patients with longer follow-up. Mean TIL cells infused was 28x109. Median IL-2 doses administered was 6.0. The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens. Conclusions: LN-145 results in 44% ORR in previously treated cervical cancer patients with acceptable safety and efficacy profile. LN-145 offers patients a viable therapeutic option warranting further investigation. Clinical trial information: NCT03108495.

OBJECTIVE: For patients with metastatic renal cell cancer (mRCC), treatment choice is mainly based on clinical parameters. With many treatments available and the limited response to treatment and associated toxicities, there is much interest in identifying better biomarkers for personalized treatment. EuroTARGET aims to identify and characterize host- and tumor-related biomarkers for prediction of response to tyrosine kinase inhibitor therapy in mRCC. Here, we describe the EuroTARGET mRCC patient cohort. METHODS AND MATERIALS: EuroTARGET is a European collaborative project designed as an observational study for which patients with mRCC were recruited prospectively in 62 centers. In addition, 462 patients with mRCC from previous studies were included. Detailed clinical information (baseline and follow-up) from all patients was entered in web-based case record forms. Blood was collected for germline DNA and pharmacokinetic/pharmacodynamic analyses and, where available, fresh-frozen tumor material was collected to perform tumor DNA, RNA, kinome, and methylome analyses. RESULTS: In total, 1,210 patients with mRCC were included. Of these, 920 received a tyrosine kinase inhibitor as first-line targeted treatment (sunitinib [N = 713, 78%], sorafenib [N = 41, 4%], or pazopanib [N = 166, 18%]) and had at least 6 months of outcome assessment (median follow-up 15.3 months [interquartile range: 8.5-30.2 months]). Germline DNA samples were available from 824 of these patients, fresh-frozen tumor material from 142 patients, fresh-frozen normal kidney tissue from 95 patients, and tissue microarrays created from formalin-fixed paraffin-embedded tumor material from 247 patients. Of the 920 patients, germline DNA variant chip data were successfully generated for 811 patients (Illumina HumanOmniExpress BeadChip). For 80 patients, next-generation exome sequencing of germline and tumor DNA was performed, tumor RNA sequencing was performed for 124 patients, kinome activity measured and processed for 121 patients (PamChip), and methylome data (Illumina Infinium HumanMethylation450 BeadChip) were created for 116 RCC tissues (and 23 normal kidney tissues). For 73 out of the 920 patients, all platform data types were generated. In addition, 40 patients were included in a pharmacokinetic/pharmacodynamic phase IV substudy. CONCLUSIONS: Analysis of EuroTARGET cohort data will contribute to personalization of therapy for patients with mRCC. The extensive clinical data and multiplatform EuroTARGET data will be freely available. We would like to thank all patients who participated and their treating physicians for inviting them. Sí

Background: \ud \ud Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma.\ud \ud Methods: \ud \ud In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0–1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete.\ud Findings: \ud \ud Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4–22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4–6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16–0·34]; p

Borderline ovarian tumours generally affect women of reproductive age. The positive prognosis is related to the fact that over 80% of cases are diagnosed at an early stage of the disease. Although radical surgery is the standard of care for this disease, fertility-sparing surgery can be performed in selected cases. Since it was first described in 1929, the knowledge of the molecular and histologic characteristics has been significantly improved. In this review, advances in the clinical behaviour, pathologic characteristics, prognostics factors, and different strategies of treatment are discussed.

522 Background: In the METEOR study (NCT01865747), cabo demonstrated improved progression-free survival (median 7.4 vs. 3.8 mo; HR 0.58, 95% CI 0.45–0.74; p