ABSTRACT
Background: In the PAOLA-1/ENGOT-ov25 (NCT02477644) primary analysis, adding ola to maintenance bev after first-line (1L) platinum-based chemotherapy (PBC) + bev led to a significant progression-free survival (PFS) benefit in AOC (HR 0.59, 95% CI 0.49-0.72;P<0.001), particularly in pts with homologous recombination deficiency (HRD+;BRCA1/2 mutation [BRCAm] and/or genomic instability;Ray-Coquard et al NEJM 2019). Here, we report the prespecified final OS analysis. Method(s): Pts with high-grade AOC, in response after PBC + bev, were randomized 2:1 to ola tablets (300 mg bid;up to 24 months [mo]) + bev (15 mg/kg q3w;15 mo total) or placebo [pbo] + bev. OS (intent-to-treat [ITT] population) was a key secondary endpoint, with analysis planned for 3 years after the primary analysis as part of hierarchical testing. Result(s): 537 pts were randomized to ola + bev and 269 to pbo + bev (median follow-up 61.7 and 61.9 mo, respectively;OS data maturity: 55.3%). Median OS in the ITT population was 56.5 mo with ola + bev vs 51.6 mo with pbo + bev (HR 0.92, 95% CI 0.76-1.12;P=0.4118;OS at 5 y, 47.3 vs 41.5%). In HRD+ pts, OS was prolonged with ola + bev (HR 0.62, 95% CI 0.45-0.85;OS at 5 y, 65.5 vs 48.4%), with benefit in HRD+ pts with or without a tumour BRCAm (tBRCAm;Table). No benefit was seen in HRD- pts (HR 1.19, 95% CI 0.88-1.63). Subsequent PARP inhibitor therapy was received by 105 (19.6%) ola + bev pts vs 123 (45.7%) pbo + bev pts. Myelodysplastic syndrome, acute myeloid leukaemia and aplastic anaemia incidence, and new primary malignancy incidence, was respectively: ola + bev, 9 pts [1.6%] and 22 pts [4.1%];pbo + bev, 6 pts [2.2%]) and 8 pts [2.9%]). [Formula presented] Conclusion(s): Despite a high proportion of pts in the control arm receiving a PARP inhibitor post-progression, ola + bev provided a clinically meaningful improvement in OS for 1L HRD+ pts with and without a tBRCAm, confirming ola + bev as standard of care in this setting. Clinical trial identification: NCT02477644. Editorial acknowledgement: Medical writing assistance was provided by Rachel Dodd, PhD, at Cence, funded by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Legal entity responsible for the study: AstraZeneca. Funding(s): ARCAGY Research, AstraZeneca, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and F. Hoffmann-La Roche. Disclosure: I.L. Ray-Coquard: Financial Interests, Personal, Advisory Board: Roche, GSK, AstraZeneca, Mersana, Deciphera, Amgen, Oxnea, Merck Sereno, Agenus, Novartis, Macrogenics, Clovis, EQRX, adaptimmun, Esai, SUTRO;Financial Interests, Institutional, Other, COLIBRI translational research: BMS;Financial Interests, Institutional, Advisory Board, translational research NEOPREMBROV trial: MSD;Non-Financial Interests, Personal, Principal Investigator: PAOLA1;Non-Financial Interests, Personal, Other, President: GINECO. K. Fujiwara: Financial Interests, Personal, Other, Consulting fees and grant support: Pfizer, Eisai, Merck Sharp & Dohme, Taiho, Zeria, Chugai Pharmaceutical, Genmab, Takeda Pharmaceutical;Financial Interests, Personal, Research Grant: Immunogen, Oncotherapy, Regeneron;Financial Interests, Personal, Other, Consulting fees: Novartis, Kyowa Hakko Kirin, Daiichi Sankyo, Mochida Pharmaceutical, NanoCarrier. A. Leary: Financial Interests, Personal, Advisory Board: Zentalis;Financial Interests, Personal, Invited Speaker, Educational: GSK, Medscape, Onko+;Financial Interests, Institutional, Other, Steering committee: MSD;Financial Interests, Institutional, Advisory Board: GSK, AZ, Clovis, Ability Pharma, MSD, Tesaro, Merck Serono, Apmonia, Blueprint;Financial Interests, Institutional, Invited Speaker, Educational: Kephren publishing;Financial Interests, Institutional, Other, Consultancy: Orion;Financial Interests, Institutional, Invited Speaker: Tesaro, AZ, Clovis;Financial Interests, Personal, Other, Consultancy: GLG;Financial Interests, Institutional, Research Grant, PI translational research: ARCAGY-GINECO, Sanofi, A ;Financial Interests, Institutional, Funding, CI clinical trial: AZ;Financial Interests, Institutional, Research Grant, Int CI clinical trial: OSE immuno;Financial Interests, Institutional, Funding, PI clinical trial: Agenus, BMS, Iovance, GSK;Financial Interests, Institutional, Funding, PI 5 clinical trials: Roche;Financial Interests, Institutional, Funding, PI 2 clinical trials: AZ;Financial Interests, Institutional, Funding, PI 3 clinical trials and steering committee: MSD;Non-Financial Interests, Institutional, Other, Academic research project: Owkin, LXRepair;Non-Financial Interests, Personal, Proprietary Information, IDMC member: Clovis;Non-Financial Interests, Personal, Proprietary Information, IDMC chair: Pfizer. S. Pignata: Financial Interests, Personal, Advisory Board: Roche, AZ, MSD, Clovis, GSK, PharmaMar;Financial Interests, Institutional, Funding: Roche, MSD, Pfizer, AZ. A.J. Gonzalez Martin: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Clovis, GSK, Genmab, Alkermes, Sutro, Roche, Sotio, PharmaMar, Oncoinvent, Novartis, Mersana, MSD, Macrogenics;Financial Interests, Personal, Invited Speaker: GSK, AstraZeneca, Clovis, Roche, Novocure, MSD;Financial Interests, Institutional, Invited Speaker, PI of ANITA trial: GSK, Roche;Financial Interests, Personal, Invited Speaker, Member of ENGOT ov43-SC: MSD;Financial Interests, Institutional, Invited Speaker, ENGOT PI of EPIK-O trial: Novartis;Financial Interests, Institutional, Invited Speaker, ENGOT PI of AVB-500 phase III trial: ARAVIVE. G. Bogner: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche and GSK;Financial Interests, Personal, Other, Medical conferences: AstraZeneca, Roche and GSK. I.B. Vergote: Financial Interests, Personal, Advisory Board, Consulting: Agenus (2021), Aksebio China (2021), AstraZeneca (2021-2022), Bristol Myers Squibb (2021), Deciphera Pharmaceuticals (2021), Eisai (2021), F. Hoffmann-La Roche Ltd. (2021), Genmab (2021), GSK (2021), Immunogen Inc. (2021-2022), Jazzpharma (2021-2022), Karyopharm (2021), MSD (2021-2022), Novocure (2020-2022), Novartis (2021), Oncoinvent AS (2021-2022), Seagen (2021), Sotio a.s. (2021-2022);Financial Interests, Institutional, Advisory Board, Consulting: AstraZeneca (2019-2020), eciphera Pharmaceuticals (2020), Elevar Therapeutics (2020), F. Hoffmann-La Roche Ltd. (2019-2020), Genmab (2019-2020), GSK (2019-2020), Mersana (2020), MSD (2019-2020), Oncoinvent AS (2019-2020), Sotio a.s. (2019-2020), Verastem Oncology (2020), Zentalis (2020), Amgen (Europe) 2019, Clovis Oncology Inc (2019), Carrick Therapeutics (2019), Millennium Pharmaceuticals (2019);Financial Interests, Institutional, Research Grant, Contracted Research ( via KU Leuven): Oncoinvent AS (2019-2020);Financial Interests, Institutional, Research Grant, Contracted Research (via KU Leuven): Genmab (2019);Financial Interests, Institutional, Research Grant, Corporate sponsored research: Amgen (2019-2020), Roche (2019-2020). N. Colombo: Financial Interests, Personal, Advisory Board, Various: Roche, PharmaMar, AstraZeneca, MSD/Merck, Clovis Oncology, Tesaro, GSK, Pfizer, Takeda, BIOCAD, Immunogen, Mersana;Financial Interests, Personal, Invited Speaker, Congress, Symposia, Lectures: AstraZeneca, Tesaro;Financial Interests, Personal, Invited Speaker, Lectures: Novartis;Financial Interests, Personal, Advisory Board, Lectures: Eisai;Financial Interests, Personal, Advisory Board, Advisory role: Nuvation Bio, Pieris;Financial Interests, Personal, Advisory Board, Advisory Role: Onxerna;Financial Interests, Institutional, Research Grant: AstraZeneca, PharmaMar, Roche;Non-Financial Interests, Personal, Other, Sterring committee member Clinical Guidelines: ESMO;Non-Financial Interests, Personal, Leadership Role, Chair, Scientific Committee: ACTO( Alleanza contro il tumore ovarico). J. Maenpaa: Financial Interests, Personal, Other, Honoraria: AstraZeneca and GSK. F. Selle: Financial Interests, Personal, Other, Honoraria: AstraZeneca, GSK Tesaro, MSD, Sandoz (Novartis), and Clovis Oncology;Financial Int rests, Institutional, Funding: Roche, GSK Tesaro, AstraZeneca, Immunogen, MSD, Incyte, and Agenus. B. Schmalfeldt: Financial Interests, Personal, Other, Honoraria: Roche, AstraZeneca, Tesaro, Clovis, GSK, MSD;Financial Interests, Personal, Advisory Role: Roche, AstraZeneca, Tesaro, Clovis, GSK, MSD;Financial Interests, Personal, Speaker's Bureau: Roche, AstraZeneca, Tesaro, Clovis, GSK, MSD;Financial Interests, Personal, Funding: Roche, AstraZeneca, Tesaro, Clovis, GSK, MSD;Financial Interests, Personal, Other, Travel or accommodation expenses: Roche, AstraZeneca, Tesaro. G. Scambia: Financial Interests, Personal, Invited Speaker, Speaker: Johnson & Johnson, AstraZeneca&MSD, Olympus Europa, Baxter Healthcare, Intuitive Surgical Inc., GlaxoSmithKline;Financial Interests, Personal, Expert Testimony, Trainer: Covidien AG (Medtronic company);Financial Interests, Institutional, Invited Speaker, 'IsoMSLN' in Ovarian Cancer and Malignant Pleural Mesothelioma: Kiromic;Financial Interests, Institutional, Invited Speaker, Roll-over study for patients who have completed a previous cancer study with olaparib and who the investigator believes can benefit from continued treatment - ROSY-O: AstraZeneca;Financial Interests, Institutional, Invited Speaker, CATCH-R: Roll-over study to provide continuous access to clinical therapy with rucaparib.: Clovis Oncology;Financial Interests, Institutional, Invited Speaker, Phase 3, multicenter, placebo-controlled clinical study comparing chemo-immunotherapy (paclitaxel-carboplatin-oregovomab) versus chemotherapy (paclitaxel-carboplatin-placebo) in patients with advanced epithelial ovarian, tubal cancer of fallopian or peritoneal (FLORA-5): Oncoquest Pharmaceuticals Inc.;Financial Interests, Institutional, Invited Speaker, Phase 2b randomized, open-label,active comparator, parallel-group, multicenter study designed to evaluate the efficacy and safety of three different doses of the P2X3 receptor antagonist (BAY 1817080) versus placebo and Elagolix 150 mg in women with symptomatic endometriosis: Bayer AG;Financial Interests, Institutional, Invited Speaker, Usability of ITE transducers for sending electric fields for tumor treatment (TTFields): Novocure Ltd.;Financial Interests, Institutional, Invited Speaker Phase III, multicentre, open-label extension trial to evaluate long-term safety and efficacy in patients with advanced cancers currently undergoing treatment or in follow-up in a pembrolizumab trial.: Merck. E.M. Guerra Alia: Financial Interests, Institutional, Invited Speaker: PharmaMar, Pfizer;Financial Interests, Personal, Invited Speaker: Pfizer. C. Lefeuvre-Plesse: Financial Interests, Personal, Advisory Role: Pfizer, AstraZeneca, Roche, and Daiichi-Sanko;Financial Interests, Personal, Other, Travel/accommodation/medical congress expenses: Roche, Novartis, Pfizer, and Pierre Fabre. A. Belau: Financial Interests, Personal, Other, Honoraria: Roche, AstraZeneca, Clovis, MSD, Daiichi Sankyo Company, Lilly, Seagen;Financial Interests, Personal, Advisory Role: Pfizer, Roche, AstraZeneca, MSD, Lilly, Daiichi Sankyo Company, Seagen;Financial Interests, Personal, Other, Travel or accommodation expenses: Roche, AstraZeneca, Daiichi Sankyo Company. A. lortholary: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD and Tesaro;Financial Interests, Personal, Speaker's Bureau: Clovis Oncology, and Roche;Financial Interests, Personal, Other, Participation in a medical congress: Novartis, Pfizer, MSD, Lilly and Roche. E. Pujade-Lauraine: Financial Interests, Personal, Other, Lecture fees: AstraZeneca, Tesaro, Roche, Clovis Oncology, Incyte, Pfizer;Financial Interests, Personal, Speaker's Bureau: AstraZeneca, Tesaro, and Roche;Financial Interests, Personal, Other, Travel/accommodation: AstraZeneca, Tesaro, and Roche;Financial Interests, Personal, Full or part-time Employment: ARCAGY Research. P. Harter: Financial Interests, Personal, Advisory Board, Value includes honoraria for lectures: AstraZeneca;Financial Interests, Personal, Advisory Board, includes honoraria for lectu es: GSK, Roche, MSD;Financial Interests, Personal, Invited Speaker: Amgen, Stryker, Zailab;Financial Interests, Personal, Advisory Board: Clovis, Immunogen;Financial Interests, Personal, Other, IDMC member: Sotio;Financial Interests, Institutional, Invited Speaker: AstraZeneca, Roche, GSK, Genmab, Immunogen;Financial Interests, Institutional, Funding: Seagen, Clovis. All other authors have declared no conflicts of interest. Copyright © 2022
ABSTRACT
In this study, the levels of fine particulate matter (PM2.5), polycyclic aromatic hydrocarbons (PAHs) and nitro-PAHs (NPAHs) in PM2.5 samples were determined from 2020 to 2021 in Singapore. For analysis convenience, the sampling period was classified according to two monsoon periods and the inter-monsoon period. Considering Singapore's typically tropical monsoon climate, the four seasons were divided into the northeast monsoon season (NE), southwest monsoon season (SW), presouthwest monsoon season (PSW) and prenortheast monsoon season (PNE)). The PM2.5 concentration reached 17.1 +/- 8.38 mu g/m(3), which was slightly higher than that in 2015, and the average PAH concentration continuously declined during the sampling period compared to that reported in previous studies in 2006 and 2015. This is the first report of NPAHs in Singapore indicating a concentration of 13.1 +/- 10.7 pg/m(3). The seasonal variation in the PAH and NPAH concentrations in PM2.5 did not obviously differ owing to the unique geographical location and almost uniform climate changes in Singapore. Diagnostic ratios revealed that PAHs and NPAHs mainly originated from local vehicle emissions during all seasons. 2-Nitropyrene (2-NP) and 2-nitrofluoranthene (2-NFR) in Singapore were mainly formed under the daytime OH-initiated reaction pathway. Combined with airmass backward trajectory analysis, the Indonesia air mass could have influenced Singapore's air pollution levels in PSW. However, these survey results showed that no effect was found on the concentrations of PAHs and NPAHs in PM2.5 in Indonesia during SW because of Indonesia's efforts in the environment. It is worth noting that air masses from southern China could impact the PAH and NPAH concentrations according to long-range transportation during the NE. The results of the total incremental lifetime cancer risk (ILCR) via three exposure routes (ingestion, inhalation and dermal absorption) for males and females during the four seasons indicated a low long-term potential carcinogenic risk, with values ranging from 10(-10) to 10(-7). This study systematically explains the latest pollution conditions, sources, and potential health risks in Singapore, and comprehensively analyses the impact of the tropical monsoon system on air pollution in Singapore, providing a new perspective on the transmission mechanism of global air pollution.