In patients with locally advanced non–small-cell lung cancer who have undergone concurrent chemotherapy and radiation therapy, the use of durvalumab in the year after completing treatment ...significantly prolonged disease-free and overall survival as compared with placebo.
The addition of pembrolizumab to chemotherapy for metastatic lung cancer without
EGFR
or
ALK
mutations resulted in better progression-free and overall survival than chemotherapy alone. Immune-related ...adverse effects were more common with the combination.
In the phase 3 KEYNOTE-024 trial, treatment with pembrolizumab conferred longer progression-free survival than did platinum-based therapy in patients with treatment-naive, advanced non-small-cell ...lung cancer (NSCLC) with a programmed cell death-ligand 1 (PD-L1) tumour proportion score of 50% or greater (PD-L1-positive). Here we report the prespecified exploratory endpoint of pembrolizumab versus chemotherapy on patient-reported outcomes (PROs).
In this multicentre, international, randomised, open-label, phase 3 trial, we recruited patients with treatment-naive, stage IV NSCLC in 102 sites in 16 countries. Eligible patients had measurable disease (per RECIST version 1.1) and an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system and integrated web response system to receive either pembrolizumab 200 mg every 3 weeks (35 cycles) or investigator-choice platinum-doublet chemotherapy (4–6 cycles or until documented disease progression or unacceptable toxicity). Randomisation was stratified according to geography, ECOG performance status, and histology. PROs were assessed at day 1 of cycles 1–3, every 9 weeks thereafter, at the treatment discontinuation visit, and at the 30-day safety assessment visit using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), the EORTC Quality of Life Questionnaire Lung Cancer 13 items (QLQ-LC13), and the European Quality of Life 5 Dimensions-3 Level (EQ-5D-3L) questionnaire. The key exploratory PRO endpoints (analysed for all patients who received at least one dose of study treatment and completed at least one PRO instrument at at least one timepoint) were baseline-to-week-15 change in the QLQ-C30 global health status (GHS)/quality-of-life (QOL) score and time to deterioration of the composite of cough, chest pain, and dyspnoea in the QLQ-LC13. This study is registered with ClinicalTrials.gov, number NCT02142738, and is ongoing but no longer enrolling patients.
Between Sept 19, 2014, and Oct 29, 2015, 305 patients were randomly assigned to pembrolizumab (n=154) or chemotherapy (n=151). Three patients in each group did not complete any PRO instruments at any timepoints, and so 299 patients were included in the full analysis set. Of these patients, one in each group did not complete any PRO instruments before week 15, and so were not included in analyses of change from baseline to week 15. PRO compliance was greater than 90% at baseline and approximately 80% at week 15 for both groups. Least-squares mean baseline-to-week-15 change in QLQ-C30 GHS/QOL score was 6·9 (95% CI 3·3 to 10·6) for pembrolizumab and −0·9 (−4·8 to 3·0) for chemotherapy, for a difference of 7·8 (2·9 to 12·8; two-sided nominal p=0·0020). Fewer pembrolizumab-treated patients had deterioration in the QLQ-LC13 composite endpoint than did chemotherapy-treated patients (46 31% of 151 patients vs 58 39% of 148 patients). Time to deterioration was longer with pembrolizumab than with chemotherapy (median not reached 95% CI 8·5 to not reached vs 5·0 months 3·6 to not reached; hazard ratio 0·66, 95% CI 0·44–0·97; two-sided nominal p=0·029).
Pembrolizumab improves or maintains health-related QOL compared with that for chemotherapy, and might represent a new first-line standard of care for PD-L1-expressing, advanced NSCLC.
Merck & Co.
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JCO
We present 5-year outcomes from the phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680). Eligible patients with previously untreated metastatic nonsquamous non-small-cell lung ...cancer without
alterations were randomly assigned 2:1 to pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles with pemetrexed and investigator's choice of carboplatin/cisplatin for four cycles, followed by maintenance pemetrexed until disease progression or unacceptable toxicity. Primary end points were overall survival (OS) and progression-free survival (PFS). Among 616 randomly assigned patients (n = 410, pembrolizumab plus pemetrexed-platinum; n = 206, placebo plus pemetrexed-platinum), median time from random assignment to data cutoff (March 8, 2022) was 64.6 (range, 60.1-72.4) months. Hazard ratio (95% CI) for OS was 0.60 (0.50 to 0.72) and PFS was 0.50 (0.42 to 0.60) for pembrolizumab plus platinum-pemetrexed versus placebo plus platinum-pemetrexed. 5-year OS rates were 19.4% versus 11.3%. Toxicity was manageable. Among 57 patients who completed 35 cycles of pembrolizumab, objective response rate was 86.0% and 3-year OS rate after completing 35 cycles (approximately 5 years after random assignment) was 71.9%. Pembrolizumab plus pemetrexed-platinum maintained OS and PFS benefits versus placebo plus pemetrexed-platinum, regardless of programmed cell death ligand-1 expression. These data continue to support pembrolizumab plus pemetrexed-platinum as a standard of care in previously untreated metastatic non-small-cell lung cancer without
alterations.
Pembrolizumab plus pemetrexed–platinum led to superior overall survival and progression-free survival, and a higher proportion of patients with a confirmed complete or partial response over placebo ...plus pemetrexed–platinum in the KEYNOTE-189 study. We aimed to evaluate prespecified exploratory patient-reported outcomes (PROs) in patients in KEYNOTE-189.
In the multicentre, double-blind, randomised, placebo-controlled, phase 3 KEYNOTE-189 study done at 126 cancer centres in 16 countries, eligible patients aged 18 years or older with histologically or cytologically confirmed metastatic non-squamous non-small-cell lung cancer without sensitising EGFR or ALK alterations, measurable disease as per Response Evaluation Criteria in Solid Tumors (version 1.1), and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled. Patients were randomly assigned (2:1) to receive intravenous pembrolizumab (200 mg) or saline placebo every 3 weeks for up to 2 years (35 cycles); all patients received four cycles of intravenous pemetrexed (500 mg/m2) with carboplatin (5 mg/mL per min) or cisplatin (75 mg/m2; investigator's choice) every 3 weeks for four cycles, followed by pemetrexed maintenance therapy every 3 weeks. Permuted block randomisation (block size six) was done with an interactive voice-response system and stratified by PD-L1 expression, choice of platinum, and smoking status. Patients, investigators, and other study personnel were unaware of treatment assignment. The European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (QLQ-C30) and Lung Cancer 13 (QLQ-LC13) were administered at cycles 1–5, every three cycles thereafter during year 1, and every four cycles during years 2–3. The primary endpoints (overall survival and progression-free survival) have been published previously. Key PRO endpoints were change from baseline to week 12 (during chemotherapy) and week 21 (following chemotherapy) in QLQ-C30 global health status/quality of life (GHS/QOL) score, and time to deterioration in cough, chest pain, or dyspnoea. PROs were analysed in all randomly assigned patients who received at least one dose of study medication and who completed at least one PRO assessment, and the results are provided with two-sided, nominal p values. This ongoing study is registered with ClinicalTrials.gov, number NCT02578680.
Between Feb 26, 2016, and March 6, 2017, 616 patients were enrolled; median follow-up was 10·5 months (range 0·2–20·4) as of data cutoff on Nov 8, 2017. 402 (99%) of 405 patients in the pembrolizumab plus pemetrexed–platinum group and 200 (99%) of 202 patients in the placebo plus pemetrexed–platinum-treated group completed at least one PRO assessment. At baseline, 359 (89%) of 402 patients in the pembrolizumab plus pemetrexed–platinum group and 180 (90%) of 200 in the placebo plus pemetrexed–platinum group were compliant with QLQ-C30; at week 12, 319 (90%) of 354 and 149 (89%) of 167 patients were compliant, respectively; and at week 21, 249 (76%) of 326 and 91 (64%) of 143 patients were compliant, respectively. From baseline to week 12, GHS/QOL scores were maintained with both pembrolizumab plus pemetrexed–platinum (least-squares mean change: 1·0 point 95% CI −1·3 to 3·2 increase) and placebo plus pemetrexed–platinum (−2·6 points −5·8 to 0·5 decrease; between-group difference: 3·6 points −0·1 to 7·2; p=0·053). From baseline to week 21, GHS/QOL scores were better maintained with pembrolizumab plus pemetrexed–platinum (least-squares mean change: 1·3 points 95% CI −1·2 to 3·6 increase) than with placebo plus pemetrexed–platinum (−4·0 points −7·7 to −0·3 decrease; between-group difference: 5·3 points 1·1 to 9·5; p=0·014). Median time to deterioration in cough, chest pain, or dyspnoea was not reached (95% CI 10·2 months to not reached) with pembrolizumab plus pemetrexed–platinum, and was 7·0 months (4·8 months to not reached) with placebo plus pemetrexed–platinum (hazard ratio 0·81 95% CI 0·60–1·09, p=0·16).
The addition of pembrolizumab to standard chemotherapy maintained GHS/QOL, with improved GHS/QOL scores at week 21 in the pembrolizumab plus chemotherapy group compared with the placebo plus chemotherapy group. These data further support use of pembrolizumab plus pemetrexed–platinum as first-line therapy for patients with metastatic non-squamous non-small-cell lung cancer.
Merck Sharp & Dohme.
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Cyclin D1 is a key cell cycle regulatory protein with demonstrated oncogenic activity in a variety of malignancies. Cyclin
D1 mRNA and protein are overexpressed in approximately 50% of primary breast ...carcinomas; however, the pathophysiological consequences
of increased expression remain unclear. To investigate the functional sequelae of cyclin D1 mRNA overexpression, we analyzed
clinical outcome in relation to the cyclin D1 mRNA level in 253 primary breast cancer patients (median follow-up, 75 months)
with particular reference to estrogen receptor (ER) status and endocrine response. Overall, with the exception of the relationship
between cyclin D1 mRNA expression and the ER, cyclin D1 mRNA was not associated with other clinicopathological features such
as age, menopausal status, axillary lymph node status, vascular invasion, tumor size, type, and grade. However, in patients
with ER-positive tumors ( n = 182), high levels of cyclin D1 mRNA were associated with increased risk of relapse ( P = 0.0016), local recurrence ( P = 0.025), metastasis ( P = 0.019), and death ( P = 0.025). In contrast, there were no clinical correlations with cyclin D1 expression in ER-negative disease ( n = 71). In 33 patients who received endocrine therapy for their primary or recurrent breast cancers, there was an apparent
association between a high cyclin D1 mRNA level and a shorter response duration within the ER-positive subgroup ( P = 0.04). Our findings indicate that overexpression of cyclin D1 mRNA correlates with a worse prognosis within the ER-positive
breast cancer phenotype and may be a contributing factor to the development of endocrine resistance in ER-positive disease.
In the ongoing, phase 3 PACIFIC trial, durvalumab improved the primary endpoints of progression-free survival and overall survival compared with that for placebo, with similar safety, in patients ...with unresectable, stage III non-small-cell lung cancer. In this analysis, we aimed to evaluate one of the secondary endpoints, patient-reported outcomes (PROs).
PACIFIC is an ongoing, international, multicentre, double-blind, randomised, controlled, phase 3 trial. Eligible patients were aged at least 18 years, had a WHO performance status of 0 or 1, with histologically or cytologically documented stage III, unresectable non-small-cell lung cancer, for which they had received at least two cycles of platinum-based chemoradiotherapy, with no disease progression after this treatment. We randomly assigned patients (2:1) using an interactive voice response system and a blocked design (block size=3) stratified by age, sex, and smoking history to receive 10 mg/kg intravenous durvalumab or matching placebo 1–42 days after concurrent chemoradiotherapy, then every 2 weeks up to 12 months. The primary endpoints of progression-free survival and overall survival have been reported previously. PROs were a prespecified secondary outcome. We assessed PRO symptoms, functioning, and global health status or quality of life in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) version 3 and its lung cancer module, the Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13) at the time of random allocation to groups, at weeks 4 and 8, every 8 weeks until week 48, and then every 12 weeks until progression. Changes from baseline to 12 month in key symptoms were analysed with mixed model for repeated measures (MMRM) and time-to-event analyses. A 10-point or greater change from baseline (deterioration or improvement) was deemed clinically relevant. This study is registered with ClinicalTrials.gov, NCT02125461, and EudraCT, 2014-000336-42.
Between May 9, 2014, and April 22, 2016, 476 patients were assigned to receive durvalumab, and 237 patients were assigned to receive placebo. As of March 22, 2018, the median follow-up was 25·2 months (IQR 14·1–29·5). More than 79% of patients given durvalumab and more than 82% of patients given placebo completed questionnaires up to week 48. Between baseline and 12 months, the prespecified longitudinal PROs of interest, cough (MMRM-adjusted mean change 1·8 95% CI 0·06 to 3·54 in the durvalumab group vs 0·7 –1·91 to 3·30 in the placebo group), dyspnoea (3·1 1·75 to 4·36 vs 1·4 –0·51 to 3·34), chest pain (−3·1 –4·57 to −1·60 vs −3·5 –5·68 to −1·29), fatigue (−3·0 –4·53 to −1·50 vs −5·2 –7·45 to −2·98), appetite loss (−5·8 –7·28 to −4·36 vs −7·0 –9·17 to −4·87), physical functioning (0·1 –1·10 to 1·28 vs 2·0 0·22 to 3·73), and global health status or quality of life (2·6 1·21 to 3·94 vs 1·8 –0·25 to 3·81) remained stable with both treatments, with no clinically relevant changes from baseline. The between-group differences in changes from baseline to 12 months in cough (difference in adjusted mean changes 1·1, 95% CI −1·89 to 4·11), dyspnoea (1·6, −0·58 to 3·87), chest pain (0·4, −2·13 to 2·93), fatigue (2·2, −0·38 to 4·78), appetite loss (1·2, −1·27 to 3·67), physical functioning (−1·9, −3·91 to 0·15), or global health status or quality of life (0·8, −1·55 to 3·14) were not clinically relevant. Generally, there were no clinically important between-group differences in time to deterioration of prespecified key PRO endpoints.
Our findings suggest that a clinical benefit with durvalumab can be attained without compromising PROs. This result is of note because the previous standard of care was observation alone, with no presumed detriment to PROs.
AstraZeneca.
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Pembrolizumab, an inhibitor of programmed cell death 1 (PD-1), produced responses in 24% of patients with non–small-cell lung cancer, with a median overall survival of 16.2 months. The response rate ...increased to 45% if more than 50% of tumor cells expressed the PD-1 ligand.
Lung cancer is the leading cause of cancer-related death worldwide.
1
,
2
Platinum-based chemotherapy, with or without maintenance therapy and subsequently followed by second-line cytotoxic chemotherapy, is standard treatment for most patients with advanced non–small-cell lung cancer, with a median survival of approximately 1 year.
3
,
4
One hallmark of cancer is immune evasion, in which the immune system does not mount an effective antitumor response.
5
Programmed cell death 1 (PD-1) is a negative costimulatory receptor expressed primarily on the surface of activated T cells.
6
,
7
The binding of PD-1 to one of its ligands, PD-L1 or PD-L2, can inhibit a cytotoxic . . .
The optical and electrical properties of a novel alcohol soluble aminoalkyl-substituted cationic conjugated polymer, ...poly9,9′-bis(6″-(N,N,N-trimethylammonium)-hexyl)fluorene-co-alt-2,5-dimethoxy-1,4-phenylene dibromide (PFPB), has been studied using absorption, photoluminescence, current–voltage–luminescence (J–V–L), and noise characterization techniques. The absorption and photoluminescence studies show that PFPB is blue-emitting, and its long alkyl side chains and two methoxy side chains introduce steric hindrance in the structure, which can minimize interchain interactions. The photoluminescence quantum efficiency of PFPB in methanol was found to be 69.6%. Polymer light emitting diodes (PLEDs) were fabricated using PFPB as an electron injection layer and device physics has been studied. The obtained device results indicate that PFPB can be used as an electron transport layer (ETL) to improve the PLED performance. The noise characteristics on the PLED devices show that the interface between the cathode and the emissive layer is improved through the introduction of a PFPB layer. Results in this report indicate that the poly(fluorene-co-phenylene)-based water/alcohol soluble cationic conjugated polymer avoids the intermixing between the electroluminance layer and adjacent ETL layer which is a common and serious problem in multilayer PLED fabrication by solution casting methods. This makes water solubility materials attractive for applications in PLEDs and other organic devices.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
1047
Background: HER2 REAL (NCT04857619) is the first multi-country, retrospective study exploring the treatment practices and outcomes in patients (pts) with HER2+ locally advanced, unresectable ...(u)/metastatic (m) breast cancer (BC) from routine clinical care in the APAC and LATAM. Methods: Adult HER2+ u/mBC pts diagnosed since reimbursement or wider access of trastuzumab emtansine (T-DM1) or 01 Jan 2017, whichever was earlier with ≥12 months (mo) of follow-up data from index date (u/mBC diagnosis) and treated with ≥1-line of therapy (LOT) were enrolled per medical chart review from 6 countries. Here we present interim descriptive analyses (cut-off 30 June 2022) on demographics, clinical characteristics, and treatment patterns. Results: Of the 763 enrolled pts, 370 with median (range) age of 55 (20–81) yrs from Hong Kong, Korea, Singapore, and Taiwan were eligible for interim analyses; 368 (99.5%) were female with 210 (57.1%) postmenopausal. A total of 210 (57.1%) pts with reported data had a median time of 2 (0–18) yrs from initial BC diagnosis to u/mBC relapse. At index date, majority had ductal carcinoma (227/254 89.4%), visceral (255/355 71.8%), and non-visceral (258/355 72.3%) metastases; 80/355 (22.5%) had CNS metastases. Family history of BC was reported by 45/370 (12.2%) pts completing the questionnaire; 209/370 (56.5%) had hormone receptor-positive BC. Treatments reported in the first to fifth line were quite variable. HER2-directed therapy was received by 323/367 (88.0%) in LOT1 (mainly trastuzumab TRA and pertuzumab PTZ-based) and 298/343 (86.9%) in LOT2 (mainly T-DM1). Median duration of LOT1 and LOT2 were 7.8 (0–130) and 5.0 (0–100) mo, respectively, that decreased to 2.3 (0–30) mo in LOT5. The prime reason for treatment discontinuation was disease progression (LOT1: 294 80.1%; LOT2: 273 79.6%; LOT3: 187 68.5%). Serious adverse effects from treatments were rare (LOT1: 7 1.9%; LOT2: 10 2.9%; LOT3: 5 1.8%). Conclusions: The interim analyses show heterogeneous treatment patterns in real-world among pts with HER2+ u/mBC progressing on HER2-directed therapies possibly due to access disparity in these 4 Asian countries. Clinical trial information: NCT04857619 . Table: see text
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