Introduction: Thyroid diseases, right after diabetes, are the most common endocrine disorder in pregnant women. Hypothyroidism occurs most frequently among all of the thyroid dysfunctions. Thyroid hormones are essential for the proper course of pregnancy and correct fetal development. Even a mild deficiency carries the risk of complications for both mother and child. It is therefore important to make a swift diagnosis, implement appropriate substitution treatment and monitor the course of the disease throughout pregnancy and in the postpartum period. Purpose of the work: The article reviews the current state of knowledge regarding maternal hypothyroidism in pregnancy. The aim of the review is to highlight the prevalence of the disease, stress the associated adverse outcomes and present the recommended management. Materials and methods: A literature research on PubMed, Cochrane Library and Google Scholar databases was done up to May 2023 with restriction to English and Polish language articles regarding hypothyroidism and pregnancy. Summary: It is extremely important to perform TSH screening tests in women planning pregnancy and during the first obstetric visit. Due to the prevalence of thyroid disorders in society, it is necessary to educate both patients and physicians. An uncomplicated diagnosis process, low cost of screening tests and available treatment methods are able to prevent the often tragic consequences of maternal hypothyroidism.
Objectives: In the open-label Phase III SOLO3 trial (NCT02282020), olaparib monotherapy provided clinically relevant and statistically significant improvements in objective response rate (ORR; primary endpoint) and progression-free survival (PFS; secondary endpoint), compared with single-agent non-platinum chemotherapy, in patients (pts) with germline BRCA1 and/or BRCA2-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) who had received ≥2 prior lines of platinum-based chemotherapy (Penson et al. JCO 2020). We report final overall survival (OS) and second disease progression results from SOLO3. Methods: Pts were randomized (2:1) to olaparib tablets (300 mg bid) or single-agent non-platinum chemotherapy treatment of physician’s choice (TPC; paclitaxel [P], topotecan [T], gemcitabine [G], or pegylated liposomal doxorubicin [PLD]). Study treatment continued until objective radiological disease progression, unacceptable toxicity, or other discontinuation criteria were met. The time from randomization to second progression or death (PFS2) and OS were secondary endpoints. As prespecified, this analysis was performed at approximately 60% data maturity for OS. Results: 266 pts were randomized (olaparib, n=178; TPC, n=88 [PLD, n=47; P, n=20; G, n=13; T, n=8]); 12 (14%) TPC pts withdrew before receiving study treatment. At the final data cut-off (DCO; April 16, 2021), 19 (11%) olaparib pts versus no TPC pts were still receiving study treatment. The percentage of pts who left the study prior to death was approximately 2.3 times higher in the TPC arm (22 pts [25%]) than in the olaparib arm (19 pts [11%]). Following disease progression, the majority of pts received subsequent anticancer therapy (119 of 178 [67%] olaparib pts vs 54 of 88 [61%] TPC pts received ≥1 subsequent anticancer regimen); three of 178 (2%) olaparib pts versus 23 of 88 (26%) TPC pts received a PARP inhibitor in their first subsequent line of therapy, with nine of 178 (5%) versus 33 of 88 (38%) pts, respectively, receiving a PARP inhibitor in any subsequent line of therapy. At the final DCO, PFS2 favored olaparib over TPC, although the between-group difference was not statistically significant, and OS was similar in the olaparib and TPC groups (see Table). Adverse events (AEs) were consistent with the known safety profile of olaparib and with previous SOLO3 analyses; no new safety signals were identified. Discontinuation of study treatment due to AEs occurred in 18 of 178 (10%) olaparib pts versus 15 of 76 (20%) TPC pts in the safety analysis set. Circulating tumor DNA analyses are ongoing. Conclusions: In the primary analysis of SOLO3, olaparib monotherapy improved ORR and PFS compared with single-agent non-platinum chemotherapy in heavily pretreated pts with gBRCAm PSROC. In the final analysis, PFS2 favored olaparib monotherapy over TPC, and OS was similar in both treatment groups, supporting the use of olaparib as a chemotherapy-free treatment option in this pt population. No new safety signals were identified. • Download : Download high-res image (68KB) • Download : Download full-size image
290 Background: The double-blind, multicenter, randomized KEYNOTE-564 study (NCT03142334) is the first positive phase 3 study of adjuvant immunotherapy for patients (pts) with renal cell carcinoma (RCC) at intermediate-high or high risk of recurrence after nephrectomy or nephrectomy and resection of metastatic lesions. Adjuvant pembrolizumab resulted in a statistically significant improvement in disease-free survival (DFS) vs placebo with 24 months of follow-up (HR 0.68, 95% CI 0.53−0.87; P = 0.0010 [one-sided]). We present updated efficacy and safety results from KEYNOTE-564 with 6 months of additional follow-up. Methods: Pts had histologically confirmed, clear cell RCC (pT2, grade 4 or sarcomatoid, N0 M0; pT3 or pT4, any grade, N0 M0; any pT, any grade, N+ M0; or M1 NED [no evidence of disease after primary tumor and soft tissue metastases completely resected ≤1 year from nephrectomy]) and had undergone surgery ≤12 weeks prior to randomization. The primary endpoint was DFS by investigator assessment in all randomized pts (ITT population). Overall survival (OS) was a key secondary endpoint. Safety/tolerability in all treated pts was a secondary endpoint. Results: 994 pts were randomized 1:1 to pembrolizumab (N = 496) or placebo (N = 498). As of data cutoff date of June 14, 2021, median (range) follow-up, defined as time from randomization to data cutoff, was 30.1 (20.8−47.5) months. In this updated analysis, DFS benefit with pembrolizumab was maintained (HR 0.63, 95% CI 0.50−0.80; nominal P < 0.0001) and was consistent across subgroups, including pts with M0 disease with intermediate-high risk of recurrence (HR 0.68, 95% CI 0.52−0.89), M0 high risk of recurrence (HR 0.60, 95% CI 0.33−1.10), or M1 NED (HR 0.28, 95% CI 0.12−0.66). The estimated DFS rate at 24 months was 78.3% with pembrolizumab vs 67.3% with placebo. A total of 66 OS events were observed, 23 in the pembrolizumab arm and 43 in the placebo arm (HR 0.52, 95% CI 0.31−0.86; P = 0.0048); the p-value did not cross the statistical hypothesis testing boundary and additional follow-up is planned for this key secondary endpoint. The estimated OS rate at 24 months was 96.2% with pembrolizumab vs 93.8% with placebo. With additional follow-up, no increase in any-grade or grade 3-4 adverse events, or steroid use for immune-mediated adverse events was observed. No deaths related to pembrolizumab occurred. Conclusions: At 30 months of follow-up, adjuvant pembrolizumab continued to demonstrate a consistent and clinically meaningful improvement in DFS vs placebo in pts with RCC at high risk of recurrence. No new safety signals were observed with pembrolizumab in the adjuvant setting. Clinical trial information: NCT03142334.
Objectives Although primary results from the IMagyn050 trial showed no statistically significant improvement in progression-free survival (PFS) with atezo added to carboplatin/paclitaxel/bevacizumab (CPB) [Moore, ESMO 2020], the impact of this regimen on selected patient (pt)-reported ovarian cancer symptoms, function, and health-related quality of life (HRQoL) is unknown and the focus of this study. Methods IMagyn050 is a double-blind randomized phase 3 trial evaluating the efficacy and safety of adding atezo/placebo to CPB followed by maintenance bevacizumab + atezo/placebo. The trial includes two cohorts: neoadjuvant chemotherapy (NACT) and primary surgery (PS). Pts complete EORTC QLQ-C30, QLQ-OV28, and FACT-G single-item GP5 at baseline (BL) and at regular intervals during treatment and follow-up. In NACT pts, prespecified responder analyses (using a ≥10-point cutoff for clinically meaningful change) assessed improvement in abdominal pain (OV28 item 31) and bloating (OV28 item 32) at week 9, comparing treatment arms by Cochran-Mantel-Haenszel (CMH) testing. Additional secondary objectives in the NACT and PS cohorts were assessments of function (physical, role, emotional, social) and HRQoL, as measured by QLQ-C30 functional and global health status/quality of life scales. Exploratory endpoints included mean change from BL in symptoms (QLQ-C30 and OV28) and treatment side-effect bother (FACT-G GP5) in both cohorts. Results Of 1301 randomized pts, completion rates for each of the 3 questionnaires were 83-100% at BL and >85% on treatment. In NACT pts, mean BL scores were similar in the atezo vs placebo arms for abdominal pain (40.2 vs 44.8) and bloating (50.4 vs 56.3). At week 9, there was no difference between treatments in the proportion of NACT pts with ≥10-point improvement in either symptom (abdominal pain: 69/136 [51%] with atezo vs 77/142 [54%] with placebo, CMH p=0.56; bloating: 74 [54%] vs 89 [63%], CMH p=0.14). Results were consistent when restricted to NACT pts with sufficient BL symptoms to show ≥10-point improvement. There was no difference between treatments in the proportion of NACT pts with improvement in function or HRQoL at week 9. In the PS cohort, similar proportions of pts in each arm showed on-treatment improvement, stabilization, or deterioration in function and HRQoL. In both cohorts, neither arm showed meaningful changes from BL in treatment-related symptoms and similar proportions of pts in both arms reported being ‘a little bit’ or ‘somewhat’ bothered by treatment side effects while on therapy. Conclusions Consistent with PFS results, there were no differences between arms in the proportion of NACT pts with a clinically meaningful improvement in abdominal pain and bloating after 3 cycles of bevacizumab-containing therapy. Pt-reported outcome analyses in both cohorts showed that adding atezo to CPB did not increase treatment burden for pts, thereby demonstrating the tolerability of this 4-drug regimen and providing further insight on the benefit-risk assessment of atezo.
LBA5 Background: Relapse after surgery for high-risk clear cell RCC (ccRCC) is associated with shortened life expectancy. Effective perioperative therapy to reduce this risk remains an unmet need. Adjuvant immune therapy is an attractive potential strategy for these pts. We conducted the KEYNOTE-564 trial to evaluate pembro vs placebo as adjuvant therapy for pts with RCC. Methods: KEYNOTE-564 is a phase III multicenter trial of pembro vs placebo in pts with histologically confirmed ccRCC, with intermediate-high risk (pT2, Gr 4 or sarcomatoid, N0 M0; or pT3, any Gr, N0 M0), high risk (pT4, any Gr, N0 M0; or pT any stage, any Gr, N+ M0), or M1 NED (no evidence of disease after primary tumor + soft tissue metastases completely resected ≤1 year from nephrectomy) (Leibovich et al, 2003; Fuhrman et al, 1982). Pts had undergone surgery ≤12 wks prior to randomization; had no prior systemic therapy; had ECOG PS 0 or 1. Study treatment was given for up to 17 cycles (≈1 yr). The primary endpoint was disease-free survival (DFS) per investigator assessment in all randomized pts (ITT population). Overall survival (OS) was a key secondary endpoint. Safety/tolerability were secondary endpoints, assessed in all treated pts. Results: Between Jun 30, 2017 and Sept 20, 2019, 994 pts were randomized 1:1 to pembro (n=496) or placebo (n=498). As of data cutoff date of Dec 14, 2020, median (range) follow-up, defined as time from randomization to data cutoff, was 24.1 (14.9−41.5) mo. No pts remain on study treatment. Baseline characteristics were generally balanced between arms. At first prespecified interim analysis, the primary endpoint of DFS was met (median not reached [NR] for both arms, HR 0.68, 95% CI 0.53−0.87; P=0.0010 [one-sided]). The estimated DFS rate at 24 mo was 77.3% with pembro vs 68.1% with placebo. Overall, DFS benefit was consistent across subgroups. A total of 51 OS events were observed (18 in the pembro arm, 33 in the placebo arm). Median OS was NR for both arms (HR 0.54, 95% CI 0.30−0.96; P=0.0164 [one-sided]); the p-value did not cross the statistical hypothesis testing boundary. The estimated OS rate at 24 mo was 96.6% with pembro vs 93.5% with placebo. 470 pts (96.3%) and 452 pts (91.1%) experienced ≥1 all-cause adverse events (AEs) with pembro vs placebo, respectively. Grade 3-5 all-cause AEs occurred in 158 pts (32.4%) with pembro and 88 pts (17.7%) with placebo. No deaths related to pembro occurred. Conclusions: Pembro demonstrated a statistically significant and clinically meaningful improvement in DFS vs placebo in pts with intermediate-high, high risk or M1 NED RCC. Additional follow-up is planned for the key secondary endpoint of OS. KEYNOTE-564 is the first positive phase III study with a checkpoint inhibitor in adjuvant RCC, and these results support pembro as a potential new standard of care for pts with RCC in the adjuvant setting. Clinical trial information: NCT03142334.
Background PD-1 blockade via pembrolizumab monotherapy has shown antitumour activity and toxicity in patients with relapsed or refractory classical Hodgkin lymphoma. Here, we present interim analyses from the KEYNOTE-204 study evaluating pembrolizumab versus brentuximab vedotin for relapsed or refractory classical Hodgkin lymphoma. Methods In this randomised, open-label, phase 3 study, patients aged 18 years or older with relapsed or refractory classical Hodgkin lymphoma with measurable disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 who were ineligible for or had relapsed after autologous haematopoietic stem-cell transplantation (HSCT) were enrolled at 78 hospitals and cancer centres in 20 countries and territories. Patients were randomly assigned (1:1) with an interactive voice response system to pembrolizumab 200 mg intravenously every 3 weeks or brentuximab vedotin 1·8 mg/kg intravenously every 3 weeks. Randomisation was stratified by previous autologous HSCT and status after front-line therapy. Results from the second interim analysis are presented here, with a database cutoff of Jan 16, 2020. The dual primary endpoints assessed in the intention-to-treat population were progression-free survival as assessed by blinded independent central review, and overall survival (not analysed at this interim analysis). Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT02684292. Recruitment for this trial is closed. Findings Between July 8, 2016, and July 13, 2018, 151 patients were randomly assigned to pembrolizumab and 153 to brentuximab vedotin. After a median time from randomisation to data cutoff of 25·7 months (IQR 23·4–33·0), median progression-free survival was 13·2 months (95% CI 10·9–19·4) for pembrolizumab versus 8·3 months (5·7–8·8) for brentuximab vedotin (hazard ratio 0·65 [95% CI 0·48–0·88]; p=0·0027). The most common grade 3–5 treatment-related adverse events were pneumonitis (six [4%] of 148 patients in the pembrolizumab group vs one [1%] of 152 patients in the brentuximab vedotin group), neutropenia (three [2%] vs 11 [7%]), decreased neutrophil count (one [1%] vs seven [5%]), and peripheral neuropathy (one [1%] vs five [3%]). Serious treatment-related adverse events occurred in 24 (16%) of 148 patients receiving pembrolizumab and 16 (11%) of 152 patients receiving brentuximab vedotin. One treatment-related death due to pneumonia occurred in the pembrolizumab group. Interpretation Pembrolizumab showed statistically significant and clinically meaningful improvement in progression-free survival compared with brentuximab vedotin, with safety consistent with previous reports. These data support pembrolizumab as the preferred treatment option for patients with relapsed or refractory classical Hodgkin lymphoma who have relapsed post-autologous HSCT or are ineligible for autologous HSCT. Funding Merck Sharp & Dohme Corp (a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA).
11 Background: Ilixadencel is a cell-based allogeneic off-the-shelf product aimed to prime anti-cancer immune response when injected intratumorally. The present randomized Phase II multicenter trial (MERECA; NCT02432846) evaluated intratumoral ilixadencel administration (2 doses 2 weeks apart) pre-nephrectomy followed by sunitinib post-nephrectomy compared with sunitinib monotherapy post-nephrectomy as first-line systemic therapy in patients with newly diagnosed synchronous metastatic renal cell carcinoma (mRCC). Methods: Patients were randomly assigned at two-to-one ratio to the combination (COMBO) or sunitinib (SUN) arm. Overall survival (OS) was assessed from enrollment while progression free survival (PFS) and tumor response was assessed per RECIST 1.1 (independent blinded central review) from start of sunitinib. Results: From April 2014 to January 2017, 88 patients (58 COMBO, 30 SUN) were randomized. In the COMBO arm, 2 patients did not receive ilixadencel, 10 did not receive sunitinib, and 1 did not have any follow up CT-scan. Five patients in the SUN arm never received sunitinib. Five patients (11%) in the COMBO arm had a complete response as best response versus one patient (4%) in the SUN arm. Confirmed ORR was 42.2 % (19/45) versus 24.0% (6/25). Median Duration of Response was 7.1 months versus 2.9 months. Median PFS was 11.8 months versus 11.0 months. Median OS has still not been reached in either group. As of July 2019, 57% and 43% were alive in the COMBO and SUN arms, respectively. Treatment with ilixadencel did not add any treatment-related Grade 3-4 Adverse Events. Conclusions: Compared to sunitinib monotherapy, combined treatment with ilixadencel followed by sunitinib demonstrated higher confirmed ORR, including several complete responses and longer duration of response, in patients with newly diagnosed synchronous mRCC. Clinical trial information: 02432846.
Background Metronomic chemotherapy (CT) is a therapeutic strategy based on a regular, short interval, fixed-dose schedule developed to improve disease control and reduce toxicity. Metronomic oral vinorelbine (m-OV) showed promising results. The trial randomly compared single agent m-OV vs OV standard schedule as first-line treatment in advanced NSCLC patients (pts) unfit for platinum-based CT (P-CT). Methods CT naive pts with advanced NSCLC unfit for P-CT (Creatinine clearance <60 ml/min; heart failure NYHA class II-III; hearing loss >G2; medical conditions impairing P-CT according to physician’s opinion) were 1:1 randomly allocated to arm A: m-OV 50mg x3/week (wk) or arm B: OV 60 mg/m²/wk cycle 1, then 80 mg/m²/wk. Primary objective: progression-free survival without grade 4 toxicity (G4PFS). Secondary objectives: disease control rate (DCR), PFS, overall survival (OS), safety, quality of life. Stratification factors: stage (IIIB vs IV), age (< 70yrs or > 70 yrs) and ECOG PS (0-1 vs 2). Results Intention-to-treat (ITT) population included 165 pts: 83 pts (A) / 82 (B). Pt characteristics were well balanced (A vs B): mean age 76.1 vs 75.9 yrs; ECOG PS 0-1: 66% vs 62%; Stage IV: 87% vs 94% pts. Median relative dose intensity was 85% vs 69%. Primary endpoint was reached (A vs B) with median G4PFS [95%CI]: 4.0 [2.6-4.3] vs 2.2 [1.5-2.9] months (mo) (p = 0.0068), HR [95%CI] = 0.63 [0.45-0.88]. Secondary efficacy end-points were as follows (A vs B): DCR 63.9% vs 63.4%; median PFS 4.3 vs 3.9 mo; median OS: 7.1 vs 7.6 mo. Treatment related AEs (r-AEs) A vs B were: all grade 61.4% vs 84%; total hematological AEs: 27.7% vs 55.6%. Most common (≥ 5%) grade 3-4 r-AEs (A vs B) were: febrile neutropenia 3.6% vs 6.2%; neutropenia 11% vs 52%; asthenia 4.8% vs 8.6%. One grade 5 AE occurred in each arm (febrile neutropenia, neutropenic sepsis). Conclusions Positive results of first randomized prospective trial: m-OV significantly improved G4PFS as first-line CT in advanced unfit NSCLC pts, with reduced toxicity. Treatment efficacy was similar in both arms. m-OV is a suitable, safe option for first-line therapy of NSCLC pts unfit to P-CT. Clinical trial identification EudraCT: 2014-003859-61. Legal entity responsible for the study Institut de Recherche Pierre Fabre- Pierre Fabre Médicament. Funding Institut de Recherche Pierre Fabre- Pierre Fabre Médicament. Disclosure A. Morabito: Speaker Bureau / Expert testimony, Speaker Bureau: Pfizer; Speaker Bureau / Expert testimony, Speaker Bureau: BMS; Speaker Bureau / Expert testimony, Speaker Bureau: Boehringer Ingelheim; Speaker Bureau / Expert testimony, Speaker Bureau: MSD; Speaker Bureau / Expert testimony, Speaker Bureau: Roche; Speaker Bureau / Expert testimony, Speaker Bureau: AstraZeneca. F. Grossi: Honoraria (self): Ely Lilly; Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Pierre Fabre; Honoraria (self): BMS; Honoraria (self): Amgen; Honoraria (self): MSD; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): MSD; Advisory / Consultancy: Ely Lilly; Advisory / Consultancy: Roche; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: BMS; Honoraria (self): Celgene. R. Ramlau: Advisory / Consultancy: Roche; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis. T. Ciuleanu: Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas Pharma; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Servier; Advisory / Consultancy, Travel / Accommodation / Expenses: A et D Pharma; Travel / Accommodation / Expenses: Ipsen. G.L. Ceresoli: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Astellas; Advisory / Consultancy: Boehringer Ingelheim. J. Bosch Barrera: Honoraria (self): Pierre Fabre; Honoraria (self): Roche; Honoraria (self): BMS; Advisory / Consultancy: Boehringer Ingelheim. P. Landreau: Full / Part-time employment: Pierre Fabre. S. Gautier: Full / Part-time employment: Pierre Fabre. C. Ta Thanh Minh: Full / Part-time employment: Pierre Fabre. A. Camerini: Speaker Bureau / Expert testimony, expert testimony: Pierre Fabre; Travel / Accommodation / Expenses: Pierre Fabre; Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.
Background Data from a randomized Phase II trial (NCT00628251) of olaparib (capsules, 200 or 400 mg bid, n=32 per arm) vs pegylated liposomal doxorubicin (PLD, n=33) in gBRCAm OC pts with recurrence ≤12 months after prior platinum therapy indicated efficacy for olaparib (Kaye et al. JCO 2012). However, the efficacy of PLD was higher than previously reported in this setting. We led a confirmatory Phase III, open-label study of olaparib vs non-platinum chemotherapy in gBRCAm PSR OC pts (NCT02282020). Methods Pts were randomized (2:1) to olaparib tablets (300 mg bid) or chemotherapy treatment of physician’s choice (TPC) (paclitaxel [P; 80 mg/m2 on day 1 (D1), D8, D15, D22 every 4 weeks (q4w)], topotecan [T; 4 mg/m2 D1, D8, D15 q4w], gemcitabine [G; 1000 mg/m2 D1, D8, D15 q4w] or PLD [50 mg/m2 D1 q4w]) until progression, stratified by: TPC, prior lines of chemotherapy (2–3 vs ≥4) and platinum-free interval (6–12 vs >12 months). Primary endpoint: ORR (blinded independent central review [BICR]). Secondary endpoints included PFS and safety. Results 266 gBRCAm PSR OC pts were randomized (olaparib, n=178; TPC, n=88 [PLD, n=47; P, n=20; G, n=13; T, n=8]); 12 in the TPC arm withdrew before receiving study treatment. 223 pts (84%) had baseline BICR measurable disease (olaparib, n=151; TPC, n=72). ORR was 72% with olaparib vs 51% with TPC (OR 2.53, 95% CI 1.40–4.58; P=0.002). HR for PFS by BICR was 0.62 (95% CI 0.43–0.91; P=0.013; median 13.4 vs 9.2 months [olaparib vs TPC]) and by investigator assessment was 0.49 (95% CI 0.35–0.70; P<0.001; median 13.2 vs 8.5 months, respectively). Most common adverse events (AEs) with olaparib were nausea (65% vs 34% [TPC]) and anemia (50% vs 25%) and with TPC were palmar-plantar erythrodysesthesia (PPE; 36% vs 1% [olaparib]) and nausea. Most common grade ≥3 AEs in either arm were anemia (21% [olaparib] vs 0 [TPC]), PPE (0 vs 12%) and neutropenia (6% vs 11%). For olaparib vs TPC, serious AEs were reported by 24% vs 18% and AEs led to treatment discontinuation in 7% vs 20%. Conclusions Pts with gBRCAm PSR OC receiving olaparib monotherapy had a significant, clinically relevant improvement in ORR and PFS vs TPC, with no new safety signals.
5506 Background: Data from a randomized Phase II trial (NCT00628251) of olaparib (capsules, 200 or 400 mg bid, n=32 per arm) vs pegylated liposomal doxorubicin (PLD, n=33) in gBRCAm OC pts with recurrence ≤12 months after prior platinum therapy indicated efficacy for olaparib (Kaye et al. JCO 2012). However, the efficacy of PLD was higher than previously reported in this setting. We led a confirmatory Phase III, open-label study of olaparib vs non-platinum chemotherapy in gBRCAm PSR OC pts (NCT02282020). Methods: Pts were randomized (2:1) to olaparib tablets (300 mg bid) or chemotherapy treatment of physician’s choice (TPC) (paclitaxel [P; 80 mg/m ² on day 1 (D1), D8, D15, D22 every 4 weeks (q4w)], topotecan [T; 4 mg/m ² D1, D8, D15 q4w], gemcitabine [G; 1000 mg/m ² D1, D8, D15 q4w] or PLD [50 mg/m ² D1 q4w]) until progression, stratified by: TPC, prior lines of chemotherapy (2–3 vs ≥4) and platinum-free interval (6–12 vs >12 months). Primary endpoint: ORR (blinded independent central review [BICR]). Secondary endpoints included PFS and safety. Results: 266 gBRCAm PSR OC pts were randomized (olaparib, n=178; TPC, n=88 [ PLD, n=47; P, n=20; G, n=13; T, n=8]); 12 in the TPC arm withdrew before receiving study treatment. 223 pts (84%) had baseline BICR measurable disease (olaparib, n=151; TPC, n=72). ORR was 72% with olaparib vs 51% with TPC (OR 2.53, 95% CI 1.40–4.58; P=0.002). HR for PFS by BICR was 0.62 (95% CI 0.43–0.91; P=0.013; median 13.4 vs 9.2 months [olaparib vs TPC]) and by investigator assessment was 0.49 (95% CI 0.35–0.70; P<0.001; median 13.2 vs 8.5 months, respectively). Most common adverse events (AEs) with olaparib were nausea (65% vs 34% [TPC]) and anemia (50% vs 25%) and with TPC were palmar-plantar erythrodysesthesia (PPE; 36% vs 1% [olaparib]) and nausea. Most common grade ≥3 AEs in either arm were anemia (21% [olaparib] vs 0 [TPC]), PPE (0 vs 12%) and neutropenia (6% vs 11%). For olaparib vs TPC, serious AEs were reported by 24% vs 18% and AEs led to treatment discontinuation in 7% vs 20%. Conclusions: Pts with gBRCAm PSR OC receiving olaparib monotherapy had a significant, clinically relevant improvement in ORR and PFS vs TPC, with no new safety signals. Clinical trial information: NCT02282020.
TPS5603 Background: There is a significant unmet need to develop new regimens for BRCA1/2-nonmutated advanced ovarian cancer (OC). The PARP inhibitor olaparib is approved for women with platinum-sensitive, recurrent OC regardless of BRCA1/2 status and, more recently, for newly diagnosed women with BRCA-mutated OC. In the TOPACIO/KEYNOTE-162 study, the combination of the PD-1–blocking antibody pembrolizumab (pembro) and niraparib demonstrated efficacy in platinum-resistant relapsed OCirrespective of BRCA1/2 status. ENGOT-OV43/KEYLYNK-001 (ClinicalTrials.gov, NCT03740165) is a phase 3, randomized, double-blind, active- and placebo-controlled study of pembro plus paclitaxel-carboplatin chemotherapy (CT) followed by olaparib maintenance for first-line treatment of patients with BRCA1/2-nonmutated advanced epithelial OC (EOC). Methods: Patients with stage III or IV BRCA-nonmutated EOC, primary peritoneal cancer, or fallopian tube cancer will be stratified by surgery status (no residual tumor after primary debulking surgery [PDS], residual tumor after PDS, or planned interval debulking), bevacizumab use, and PD-L1 status (combined positive score < 10 or ≥10). After one lead-in cycle of CT, patients will be randomized 1:1:1 to receive: CT + pembro followed by olaparib maintenance; CT + pembro followed by placebo; or CT + placebo followed by placebo. The CT regimen will be administered for 5 cycles, and pembro 200 mg Q3W will be administered for 35 infusions. Olaparib 300 mg BID maintenance therapy will start after the end of CT as concomitant treatment with pembro until discontinuation or for 2 years if the patient has a complete response. Bevacizumab use is permitted at investigator’s discretion and determined prerandomization. Primary endpoints are investigator-assessed progression-free survival (PFS) per RECIST 1.1 criteria and overall survival. Key secondary endpoints are PFS per RECIST 1.1 assessed by blinded independent central review, PFS after next-line treatment, and safety. Enrollment is currently ongoing. Clinical trial information: NCT03740165.
Autologous hematopoietic stem cell transplantation (autoHSCT) requires collection of sufficient number of hematopoietic stem cells. The goal of this study was to evaluate efficacy of plerixafor used in patients with lymphoid malignancies failing conventional stem cell mobilization. This was a prospective, non-interventional study. All consecutive patients (n = 109) treated with plerixafor in 11 centers were reported. The drug was used either in case of previous mobilization failure (n = 67) or interventionally, in case of insufficient CD34 ⁺ cell output during current mobilization (n = 42). Successful mobilization was defined as resulting in collection of ≥ 2 × 10 ⁶ CD34 ⁺ cells/kg for single autoHSCT or ≥ 4 × 10 ⁶ CD34 ⁺ cells/kg for double procedure. The overall rate of successful mobilization was 55% (55% for single and 56% for double autoHSCT). The median total number of collected CD34 ⁺ cells/kg was 2.4 (range, 0-11.5) for patients intended for a single transplantation while 4.0 (0.6-16.9) for double procedure. The number of circulating CD34 ⁺ cells increased after the use of plerixafor regardless of baseline values. The median fold increase was 3.3 (0.3-155). Data from this observational study confirm high efficacy of plerixafor used in routine clinical practice as salvage for patients with lymphoid malignancies failing conventional stem cell mobilization.
Purpose: To test the hypothesis that contact lens sensor (CLS)-based 24-hour profiles of ocular volume changes contain information complementary to intraocular pressure (IOP) to discriminate between primary open angle glaucoma (POAG) and healthy (H) eyes. Design: Development and evaluation of a diagnostic test with machine learning. Subjects: From 435 subjects (193 healthy and 242 POAG), 136 POAG and 136 age-matched healthy subjects were selected. Subjects with contraindications for CLS wear were excluded. Methods: This is a pooled analysis of data from 24 prospective clinical studies and a registry. All subjects underwent 24-hour CLS recording on one eye. Statistical and physiological CLS parameters were derived from the signal recorded. CLS parameters frequently associated with the presence of POAG were identified using a random forest modelling approach. Main outcome measures: Area under the receiver operating characteristic curve (ROC AUC) for feature sets including CLS parameters, Start IOP as well as a feature set with CLS parameters and Start IOP combined. Results: The CLS parameters feature set discriminated POAG from H eyes with mean ROC AUCs of 0.611, confidence interval (CI) 0.493-0.722. Larger values of a given CLS parameter were in general associated with a diagnosis of POAG. The Start IOP feature set discriminated between POAG and H eyes with a mean ROC AUC of 0.681, CI 0.603-0.765. The combined feature set was the best indicator of POAG with a ROC AUC of 0.759, CI 0.654-0.855. This ROC AUC was statistically higher than for CLS parameters or Start IOP feature sets alone (both p<0.0001). Conclusions: CLS recordings contain information complementary to IOP that enable discrimination between H and POAG. The feature set combining CLS parameters and Start IOP provide a better indication of the presence of POAG than each of the feature sets separately. As such, the CLS may be a new biomarker for POAG.
A ease report of a 50-em diameter and 20-kg mass of benign ovarian tumor. Total abdominal hysterectomy with a bilateral salpingo- oophorectomy was performed with full patient recovery. Fibrothecomas can remain long asymptomatic and can grow to giant sizes.
Aim: Under the supervision of the Department of General and Vascular Surgery of Poznan University of Medical Sciences, a questionnaire was distributed online or as a paper version to medical students (MSs) in order to better understand the attitudes towards surgery as a specialty and to determine the reasons why students do and do not choose vascular surgery as their career path. Materials and methods: The questionnaire was distributed online or as a paper version to MSs in the 3rd, 5th, and 6th year of the PUMS 6-year M.D. Program: It provided the data on the year of study, grade point average (GPA), sex, age, respondent's specialty choice, 33 questions with responses on a 1-5 Likert scale (1 was the least important reason and 5 was the most important reason), and 2 questions with socres between 0 and 4. A total of 136 Polish MSs of PUMS completed the survey. Results: For MSs who choose vascular surgery as their career path, "endovascular capabilities of vascular surgery" and "higher income possibilities than a general surgeon" were the most important reasons. The "poor availability of work in other places than the vascular surgery department of your choice, few such clinics in the region" was the most important reason not to choose vascular surgery. A role of gender was also noted - 13% of male MSs classified gender as an "important factor", in contrast to 60% of female MSs. Conclusions: The findings of this study might help to develop better strategies to attract future trainees to surgical specialties, particularly vascular surgery, and improve work environment.
Background: Iliac/common femoral vein obstruction (ICFVO) can cause both severe venous insufficiency and significant patient morbidity. When identified, treatment with percutaneous angioplasty and stent can be life changing. Both multiplanar venography and intravascular ultrasound are used to diagnose ICFVO and to guide intervention. This study was designed to (1) prospectively compare the diagnostic performance of con ventional multiplanar venography vs intravascular ultrasound (IVUS) for diagnosing and treating ICFVO; and (2) to characterize the patient response to iliofemoral vein intervention (ie, clinical improvement, quality of life [QoL]) over 6 months of follow up. Methods: In a prospective, multicenter, single arm study, patients (clinical class CEAP C4 C6) underwent invasive assessment for ICFVO and possible endovascular intervention. In patients with bilateral disease, the more severely affected leg was designated the study limb. Exclusion criteria were prior venous stents, venovenous bypass surgery, known chronic total occlusion; severe superficial venous reflux; acute deep vein thrombosis, history of thrombophilia; and elevated serum creatinine. All patients under went multiplanar (ie, AP, RAO, LAO) venography of the study leg, and a treatment strategy based on the venograms was documented. All patients then underwent IVUS evaluation of the study leg, and the final treatment strategy was documented. Completion multiplanar venography and IVUS was performed after any intervention. Significant ICFVO was (1) 50% diam eter stenosis on venogram, (2) 50% cross sectional area stenosis on IVUS, (3) webs or collaterals. Duplex ultrasound, CEAP class, Venous Clinical Severity Score (VCSS), QoL questionnaires (ie, SF 36v2, CIVIQ 14), and ulcer measurements were performed at baseline, 1 month and 6 month follow up visits. Results: Between July, 2014 and July, 2015, 100 patients were enrolled at 11 U.S. and three European centers. Median age was 63 years (range, 30 85 years); 43% were women; left right study leg distribution was 63:37. Baseline parameters were CEAP: C4 (35%), C5 (15%), C6 (50%); VCSS (scale 0 30) 14.5 6 4.8 (mean 6 SD); CIVIQ 14 (scale 0 100) 54.9 6 23.9 (mean 6 SD). The Table summarizes lesion detection by modality. IVUS detected significantly more lesions than multiplanar venography (P < .0001 by Wilcoxon signed rank test). No adverse device effects were reported. Conclusions: This is the first prospective, multicenter study comparing venography vs IVUS for diagnosing venous outflow obstruction. IVUS detected nearly twice as many ICFVO than multiplanar venography (P < .0001) in a cohort of patients with advanced venous insufficiency. Data regarding lesion characteristics, stent sizing, treatment plan changes based on venogram vs IVUS, and clinical/QoL response to intervention will be available for report at the end of 2015.
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