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The role of thromboxane A2 (TxA2) in smoking-associated lung cancer is poorly understood. This study was conducted to study the role of TxA2 in smoking carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-promoted cell survival and growth in human lung cancer cells. We found that NNK increased TxA2 synthase (TxAS) expression and thromboxane B2 (TxB2) generation in cultured lung cancer cells, the result of which was supported by the increased level of TxAS in lung cancer tissues of smokers. Both TxAS-specific inhibitor furegrelate and TxA2 receptor antagonist SQ29548 completely blocked NNK-mediated cell survival and growth via inducting apoptosis. TxA2 receptor agonist U46619 reconstituted a near-full survival and growth response to NNK when TxAS was inhibited, affirming the role of TxA2 receptor in NNK-mediated cell survival and growth. Suppression of cyclic adenosine monophosphate response element binding protein (CREB) activity by its small interference RNA blocked the effect of NNK. Phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) also had a positive role. Altogether, our results have revealed that NNK stimulates TxA2 synthesis and activates its receptor in lung cancer cells. The increased TxA2 may then activate CREB through PI3K/Akt and extracellular ERK pathways, thereby contributing to the NNK-promoted survival and growth of lung cancer cells. [ABSTRACT FROM AUTHOR]

Background The ongoing phase III ARCHER 1050 study (NCT01774721) compared dacomitinib (daco) with gefitinib (gef) as first-line therapy for pts with advanced epidermal growth factor receptor-positive (EGFR+) non-small cell lung cancer (NSCLC). Progression-free survival, duration of response, and OS significantly improved with daco vs gef. The improvement in OS was previously reported after median follow-up of 31.3 months (mo) with 220 (48.7%) total deaths. Here, final OS results are reported after a median follow-up of 47.9 mo in ARCHER 1050 to evaluate the persistence of OS improvement with daco. Methods Pts with newly diagnosed EGFR+ NSCLC were randomized 1:1 to daco or gef. Randomization was stratified by race and EGFR mutation type. Results Over a median follow-up of 47.9 mo as of 13 May 2019, 285 deaths occurred (133 [58.6%] in the daco arm [n = 227] and 152 [67.6%] in the gef arm [n = 225]). OS was still significantly improved with daco vs gef (stratified hazard ratio [HR], 0.748; 95% confidence interval [CI], 0.591–0.947; 2-sided P = 0.0155). Median OS (95% CI) with daco was 34.1 mo (29.5–39.8) vs 27.0 mo (24.4–31.6) with gef. OS30 was 56.4% with daco and 45.7% with gef. Median OS, unstratified HR, and P values for interaction are also reported by race and EGFR mutation type (Table). Dose reductions occurred in 154 (67.8%) pts receiving daco; median OS (95% CI) in pts with and without dose reductions was 42.5 (36.7–not estimable [NE]) and 20.7 (15.4–25.6) mo, respectively. In pts reduced to a lowest daco dose of 30 mg (n = 89) and 15 mg (n = 65), median OS was 36.7 mo (28.8–44.7) and NE (40.1 mo–NE), respectively. Conclusions With extended follow-up (median 47.9 mo), daco continues to improve OS over gef in pts with advanced EGFR+ NSCLC; the same trend was observed in most subgroups defined by race and EGFR status. The benefit of OS was maintained in patients who received dose reductions. Table: LBA19 Overall survival by demographics (ITT population)   Events/N (%)   Median a (month)   HR (95% CI) (Unstratified)  P b   Daco  Gef  Daco  Gef  Overall  133/227 (58.6)  152/225 (67.6)  34.1  27.0  0.775 (0.614–0.978)    Race per CRF Asian Mainland Chinese Japanese other East Asian Non-Asian  95/170 (55.9) 69/114 (60.5) 22/40 (55.0) 4/16 (25.0) 38/57 (66.7)  115/176 (65.3) 87/117 (74.4) 22/41 (53.7) 6/18 (33.3) 37/49 (75.5)  37.7 32.5 42.2 NE 29.5  29.1 24.9 44.8 NE 20.6  0.759 (0.578–0.996) 0.687 (0.501–0.943) 0.985 (0.546–1.780) 0.787 (0.222–2.791) 0.758 (0.480–1.196)  0.9886 c   EGFR at randomization Exon 19 deletion Exon 21 L858R substitution mutation  73/134 (54.5) 60/93 (64.5)  82/133 (61.7) 70/92 (76.1)  36.7 32.5  30.8 23.2  0.847 (0.618, 1.161) 0.665 (0.470, 0.941)  0.3292    Events/N (%)   Median a (month)   HR (95% CI) (Unstratified)  P b   Daco  Gef  Daco  Gef  Overall  133/227 (58.6)  152/225 (67.6)  34.1  27.0  0.775 (0.614–0.978)    Race per CRF Asian Mainland Chinese Japanese other East Asian Non-Asian  95/170 (55.9) 69/114 (60.5) 22/40 (55.0) 4/16 (25.0) 38/57 (66.7)  115/176 (65.3) 87/117 (74.4) 22/41 (53.7) 6/18 (33.3) 37/49 (75.5)  37.7 32.5 42.2 NE 29.5  29.1 24.9 44.8 NE 20.6  0.759 (0.578–0.996) 0.687 (0.501–0.943) 0.985 (0.546–1.780) 0.787 (0.222–2.791) 0.758 (0.480–1.196)  0.9886 c   EGFR at randomization Exon 19 deletion Exon 21 L858R substitution mutation  73/134 (54.5) 60/93 (64.5)  82/133 (61.7) 70/92 (76.1)  36.7 32.5  30.8 23.2  0.847 (0.618, 1.161) 0.665 (0.470, 0.941)  0.3292  a Kaplan-Meier estimate; b P interaction; c P for interaction of treatment by Asian vs non-Asian CI, confidence interval; CRF, case report form; daco, dacomitinib; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EGFR, epidermal growth factor receptor; gef, gefitinib; HR, Hazard ratio; ITT, intention-to-treat, NE, not estimable. Table: LBA19 Overall survival by demographics (ITT population)   Events/N (%)   Median a (month)   HR (95% CI) (Unstratified)  P b   Daco  Gef  Daco  Gef  Overall  133/227 (58.6)  152/225 (67.6)  34.1  27.0  0.775 (0.614–0.978)    Race per CRF Asian Mainland Chinese Japanese other East Asian Non-Asian  95/170 (55.9) 69/114 (60.5) 22/40 (55.0) 4/16 (25.0) 38/57 (66.7)  115/176 (65.3) 87/117 (74.4) 22/41 (53.7) 6/18 (33.3) 37/49 (75.5)  37.7 32.5 42.2 NE 29.5  29.1 24.9 44.8 NE 20.6  0.759 (0.578–0.996) 0.687 (0.501–0.943) 0.985 (0.546–1.780) 0.787 (0.222–2.791) 0.758 (0.480–1.196)  0.9886 c   EGFR at randomization Exon 19 deletion Exon 21 L858R substitution mutation  73/134 (54.5) 60/93 (64.5)  82/133 (61.7) 70/92 (76.1)  36.7 32.5  30.8 23.2  0.847 (0.618, 1.161) 0.665 (0.470, 0.941)  0.3292    Events/N (%)   Median a (month)   HR (95% CI) (Unstratified)  P b   Daco  Gef  Daco  Gef  Overall  133/227 (58.6)  152/225 (67.6)  34.1  27.0  0.775 (0.614–0.978)    Race per CRF Asian Mainland Chinese Japanese other East Asian Non-Asian  95/170 (55.9) 69/114 (60.5) 22/40 (55.0) 4/16 (25.0) 38/57 (66.7)  115/176 (65.3) 87/117 (74.4) 22/41 (53.7) 6/18 (33.3) 37/49 (75.5)  37.7 32.5 42.2 NE 29.5  29.1 24.9 44.8 NE 20.6  0.759 (0.578–0.996) 0.687 (0.501–0.943) 0.985 (0.546–1.780) 0.787 (0.222–2.791) 0.758 (0.480–1.196)  0.9886 c   EGFR at randomization Exon 19 deletion Exon 21 L858R substitution mutation  73/134 (54.5) 60/93 (64.5)  82/133 (61.7) 70/92 (76.1)  36.7 32.5  30.8 23.2  0.847 (0.618, 1.161) 0.665 (0.470, 0.941)  0.3292  a Kaplan-Meier estimate; b P interaction; c P for interaction of treatment by Asian vs non-Asian CI, confidence interval; CRF, case report form; daco, dacomitinib; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EGFR, epidermal growth factor receptor; gef, gefitinib; HR, Hazard ratio; ITT, intention-to-treat, NE, not estimable. Clinical trial identification NCT01774721. Editorial acknowledgement Jessica Yuan (inScience Communications, Springer Healthcare, New York, NY, USA). Legal entity responsible for the study Pfizer Inc. Funding Pfizer Inc. and SFJ Pharmaceuticals® Disclosure T.S.K. Mok: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: ACEA Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Alpha Biopharma Co. Ltd.; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amoy Diagnostics Co. Ltd.; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, before 1/1/19: AstraZeneca ; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: BI; Honoraria (self), Advisory / Consultancy: Blueprint Medicines Corporation; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: CStone Pharmaceuticals; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Honoraria (self), Advisory / Consultancy: Fishawack Facilitate Ltd; Honoraria (self), Advisory / Consultancy: Hengrui Therapeutics Inc.; Honoraria (self), Advisory / Consultancy: Ignyta, Inc.; Honoraria (self), Advisory / Consultancy, Sept 2019: Incyte Corporation; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: InMed Medical Communication; Honoraria (self), Advisory / Consultancy, Jun 2019: Iqvia; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Loxo-Oncology; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy: MoreHealth; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: OncoGenex Pharmaceuticals, Inc.; Honoraria (self), Advisory / Consultancy: OrigiMed; Honoraria (self), Advisory / Consultancy: PeerVoice; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: PrIME Oncology; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche/Genentech; Honoraria (self), Advisory / Consultancy: Sanofi-Aventis R&D; Honoraria (self), Advisory / Consultancy: SFJ Pharmaceutical Ltd.; Honoraria (self), Advisory / Consultancy: Takeda Pharmaceuticals HK Ltd.; Honoraria (self), Advisory / Consultancy: Vertex Pharmaceuticals; Honoraria (self), Advisory / Consultancy: Yuhan Corporation; Advisory / Consultancy: Cirina; Advisory / Consultancy, uncompensated: GeneDecode Co. Ltd.; Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Takeda Oncology; Leadership role, Officer / Board of Directors, Remunerated: AstraZeneca PLC; Leadership role, Officer / Board of Directors, Remunerated: Hutchison Chi-Med; Leadership role, Officer / Board of Directors, Non-remunerated: American Society of Clinical Oncology; Leadership role, Officer / Board of Directors, Non-remunerated: Asian Thoracic Oncology Research Group ; Leadership role, Officer / Board of Directors, Non-remunerated: Chinese Lung Cancer Research Foundation Limited; Leadership role, Officer / Board of Directors, Non-remunerated: Chinese Society of Clinical Oncology; Leadership role, Officer / Board of Directors, Non-remunerated: Hong Kong Cancer Fund; Leadership role, Officer / Board of Directors, Non-remunerated: Hong Kong Cancer Therapy Society ; Leadership role, Officer / Board of Directors, term ended on 30/4/19: International Association for the Study of Lung Cancer ; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Roche; Research grant / Funding (institution): SFJ; Research grant / Funding (institution): XCovery; Shareholder / Stockholder / Stock options, Shareholder: Hutchison Chi-Med; Shareholder / Stockholder / Stock options, Shareholder: Sanomics Ltd.; Shareholder / Stockholder / Stock options, now Biolidics Ltd.; Stock option: Clearbridge Biomedics; Shareholder / Stockholder / Stock options, Stock option: Loxo-Oncology; Shareholder / Stockholder / Stock options, Stock option: OrigiMed Co. Ltd.; Shareholder / Stockholder / Stock options, Stock option: Virtus Medical Group; Research grant / Funding (institution): AstraZeneca. K.H. Lee: Advisory / Consultancy: MSD; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS. K. Nakagawa: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma Inc.; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Takeda Pharmaceutical Co. Ltd; Honoraria (self), Research grant / Funding (institution): AstraZeneca K.K.; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): MSD K.K.; Honoraria (self), Research grant / Funding (institution): Eli Lilly Japan K.K.; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Nippon Boehringer Ingelheim Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Novartis Pharma K.K.; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Pfizer Japan Inc.; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb Company; Honoraria (self): Nikkei Business Publications, Inc.; Honoraria (self): Kyorin Pharmaceutical Co. Ltd.; Honoraria (self): Medicus Shuppan, Publishers Co. Ltd.; Honoraria (self): CareNet, Inc; Honoraria (self): Thermo Fisher Scientific K.K.; Honoraria (self): Nichi-Iko Pharmaceutical Co. Ltd.; Honoraria (self): Nanzando Co. Ltd; Honoraria (self): Hisamitsu Pharmaceutical Co. Inc; Honoraria (self): Medical Review Co. Ltd.; Honoraria (self): Yodosha Co. Ltd; Honoraria (self): Yomiuri Telecasting Corporation; Research grant / Funding (institution): Icon Japan K.K.; Research grant / Funding (institution): Quintiles Inc.; Research grant / Funding (institution): CMIC Shift Zero K.K.; Research grant / Funding (institution): Eisai Co. Ltd.; Research grant / Funding (institution): Parexel International Corp.; Research grant / Funding (institution): Kissei Pharmaceutical Co. Ltd.; Research grant / Funding (institution): Iqvia; Research grant / Funding (institution): Kyowa Hakko Kirin Co. Ltd; Research grant / Funding (institution): EPS Corporation; Research grant / Funding (institution): SymBio Pharmaceuticals Limited; Research grant / Funding (institution): Bayer Yakuhin, Ltd; Research grant / Funding (institution): Merck Serono Co. Ltd.; Research grant / Funding (institution): A2 Healthcare Corp.; Research grant / Funding (institution): AbbVie Inc.. S. Niho: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self): Chugai; Honoraria (self): Taiho; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Eli Lilly; Honoraria (self): Novartis; Honoraria (self): Boehringer Ingelheim; Research grant / Funding (institution): Merck Serono. R. Linke: Full / Part-time employment: SFJ Pharmaceuticals®. M.R. Migliorino: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BI; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche. A. Pluzanski: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche. K. Noonan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. Y. Tang: Full / Part-time employment: Pfizer Inc. K.D. Wilner: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc. Y. Wu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): MSD; Honoraria (self): BMS. [ABSTRACT FROM AUTHOR]

Background In the ongoing phase 3 comparison of dacomitinib (daco) and gefitinib (gef) (ARCHER 1050; NCT01774721) as first-line therapy for EGFR-mutation-positive (EGFR+) advanced NSCLC, daco was associated with significant improvement in progression free survival (PFS) and overall survival (OS). Here we present results for the subset of Asian patients (pts). Methods Eligible pts with newly diagnosed stage IIIB/IV or recurrent EGFR+ advanced NSCLC were randomized (1:1) to oral daco 45 mg once daily or gef 250 mg. Randomization was stratified by race and EGFR mutation (exon 19 del/exon 21 L858R) status. The primary efficacy endpoint was PFS by blinded independent radiologic central review (BIRC). Secondary endpoints were OS, objective response rate (ORR) and duration of response (DOR) by BIRC, and safety. Results Of 346 Asian pts, 170 were randomized to daco treatment and 176 to gef. Demographics and baseline characteristics of the groups were well balanced. At the July 29, 2016 data cutoff, the hazard ratio for PFS was 0.510 (95% confidence interval [CI] 0.392, 0.664), favoring daco (2-sided p value < 0.0001). Median PFS was 16.5 months (95% CI 12.9, 18.4) for daco and 9.3 months for gef (95% CI 9.2, 11.0). OS, ORR and DOR are shown in the table. Treatment-related adverse events (TRAEs) occurring in ≥ 50% of daco-treated pts were diarrhea (88.2%), paronychia (64.7%), and dermatitis acneiform (56.5%). In the gef arm, diarrhea (52.3%) was the only TRAE that occurred in ≥ 50% of pts. The daco dose was reduced in 67.6% of pts associated with adverse events (AEs); gef dose was reduced to every other day dosing in 9.7% of pts associated with AEs. Conclusions First-line daco was associated with significant prolongation of PFS compared with gef in Asian pts with EGFR+ advanced NSCLC. Daco treatment showed improved OS, ORR, and DOR compared to gef treatment. The AE profile for daco and gef in Asian pts was consistent with the overall ARCHER 1050 study. Table: 480P Key secondary endpoints   Dacomitinib N = 170  Gefitinib N = 176  Median overall survival, months (95% CI) a   34.2 (30.1, NE  29.1 (25.2,NE)  Objective response rate, % (95% CI)  77.1 (70.0, 83.1)  72.7 (65.5, 79.2)  ---Patients with complete response (n, %)  9 (5.3)  4 (2.3)  ---Patients with partial response (n, %)  122 (71.8)  124 (70.5)  Median duration of response, months (95% CI)  16.6 (13.8, 30.4)  8.3 (8.1, 10.2)    Dacomitinib N = 170  Gefitinib N = 176  Median overall survival, months (95% CI) a   34.2 (30.1, NE  29.1 (25.2,NE)  Objective response rate, % (95% CI)  77.1 (70.0, 83.1)  72.7 (65.5, 79.2)  ---Patients with complete response (n, %)  9 (5.3)  4 (2.3)  ---Patients with partial response (n, %)  122 (71.8)  124 (70.5)  Median duration of response, months (95% CI)  16.6 (13.8, 30.4)  8.3 (8.1, 10.2)  CI, confidence interval; N/n;number of patients; NE; not estimable. a Feb 17, 2017 was the data cutoff for final OS analysis. Table: 480P Key secondary endpoints   Dacomitinib N = 170  Gefitinib N = 176  Median overall survival, months (95% CI) a   34.2 (30.1, NE  29.1 (25.2,NE)  Objective response rate, % (95% CI)  77.1 (70.0, 83.1)  72.7 (65.5, 79.2)  ---Patients with complete response (n, %)  9 (5.3)  4 (2.3)  ---Patients with partial response (n, %)  122 (71.8)  124 (70.5)  Median duration of response, months (95% CI)  16.6 (13.8, 30.4)  8.3 (8.1, 10.2)    Dacomitinib N = 170  Gefitinib N = 176  Median overall survival, months (95% CI) a   34.2 (30.1, NE  29.1 (25.2,NE)  Objective response rate, % (95% CI)  77.1 (70.0, 83.1)  72.7 (65.5, 79.2)  ---Patients with complete response (n, %)  9 (5.3)  4 (2.3)  ---Patients with partial response (n, %)  122 (71.8)  124 (70.5)  Median duration of response, months (95% CI)  16.6 (13.8, 30.4)  8.3 (8.1, 10.2)  CI, confidence interval; N/n;number of patients; NE; not estimable. a Feb 17, 2017 was the data cutoff for final OS analysis. Clinical trial identification NCT01774721. Editorial acknowledgement Medical writing support was provided by Michelle Daniels (inScience Communications, Springer Healthcare, Philadelphia, PA, USA). Legal entity responsible for the study Pfizer Inc. Funding Pfizer Inc. Disclosure T.S.K. Mok: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: ACEA Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Alpha Biopharma Co. Ltd.; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amoy Diagnostics Co. LTD.; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, before 1/1/19: AstraZeneca; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: BI; Honoraria (self), Advisory / Consultancy: Blueprint Medicines Corporation; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: CStone Pharmaceuticals; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Honoraria (self), Advisory / Consultancy: Fishawack Facilitate Ltd; Honoraria (self), Advisory / Consultancy: Hengrui Therapeutics Inc.; Honoraria (self), Advisory / Consultancy: Ignyta, Inc.; Honoraria (self), Advisory / Consultancy, Sept 2019: Incyte Corporation; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: InMed Medical Communication; Honoraria (self), Advisory / Consultancy, Jun 2019: IQVIA; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Loxo-Oncology; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy: MoreHealth; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: OncoGenex Pharmaceuticals, Inc.; Honoraria (self), Advisory / Consultancy: OrigiMed; Honoraria (self), Advisory / Consultancy: PeerVoice; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: PrIME Oncology; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche/Genentech; Honoraria (self), Advisory / Consultancy: Sanofi-Aventis R&D; Honoraria (self), Advisory / Consultancy: SFJ Pharmaceutical Ltd.; Honoraria (self), Advisory / Consultancy: Takeda Pharmaceuticals HK Ltd.; Honoraria (self), Advisory / Consultancy: Vertex Pharmaceuticals; Honoraria (self), Advisory / Consultancy: Yuhan Corporation; Advisory / Consultancy: Cirina; Advisory / Consultancy, uncompensated: geneDecode Co. Ltd.; Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Takeda Oncology; Leadership role, Officer / Board of Directors, Remunerated: AstraZeneca PLC; Leadership role, Officer / Board of Directors, Remunerated: Hutchison Chi-Med; Leadership role, Officer / Board of Directors, Non-remunerated: American Society of Clinical Oncology; Leadership role, Officer / Board of Directors, Non-remunerated: Asian Thoracic Oncology Research Group; Leadership role, Officer / Board of Directors, Non-remunerated: Chinese Lung Cancer Research Foundation Limited; Leadership role, Officer / Board of Directors, Non-remunerated: Chinese Society of Clinical Oncology; Leadership role, Officer / Board of Directors, Non-remunerated: Hong Kong Cancer Fund; Leadership role, Officer / Board of Directors, Non-remunerated: Hong Kong Cancer Therapy Society; Leadership role, Officer / Board of Directors, term ended on 30/4/19: International Association for the Study of Lung Cancer ; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Roche; Research grant / Funding (institution): SFJ; Research grant / Funding (institution): XCovery; Shareholder / Stockholder / Stock options, Shareholder: Hutchison Chi-Med; Shareholder / Stockholder / Stock options, Shareholder: Sanomics Ltd.; Shareholder / Stockholder / Stock options, now Biolidics Ltd.; Stock option: Clearbridge Biomedics; Shareholder / Stockholder / Stock options, Stock option: Loxo-Oncology; Shareholder / Stockholder / Stock options, Stock option: OrigiMed Co. Ltd.; Shareholder / Stockholder / Stock options, Stock option: Virtus Medical Group; Research grant / Funding (institution): AstraZeneca. K.H. Lee: Advisory / Consultancy: MSD; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS. K. Nakagawa: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma Inc.; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Takeda Pharmaceutical Co. Ltd; Honoraria (self), Research grant / Funding (institution): AstraZeneca K.K.; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical Co.Ltd.; Honoraria (self), Research grant / Funding (institution): MSD K.K.; Honoraria (self), Research grant / Funding (institution): Eli Lilly Japan K.K.; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Nippon Boehringer Ingelheim Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Novartis Pharma K.K.; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Pfizer Japan Inc.; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self): Nikkei Business Publications, Inc.; Honoraria (self): Kyorin Pharmaceutical Co. Ltd.; Honoraria (self): Medicus Shuppan, Publishers Co. Ltd.; Honoraria (self): CareNet, Inc.; Honoraria (self): Thermo Fisher Scientific K.K.; Honoraria (self): Nichi-Iko Pharmaceutical Co. Ltd.; Honoraria (self): Nanzando Co. Ltd; Honoraria (self): Hisamitsu Pharmaceutical Co. Inc; Honoraria (self): Medical Review Co. Ltd.; Honoraria (self): Yodosha Co. Ltd; Honoraria (self): Yomiuri Telecasting Corporation; Research grant / Funding (institution): ICON Japan K.K.; Research grant / Funding (institution): Quintiles Inc.; Research grant / Funding (institution): CMIC Shift Zero K.K.; Research grant / Funding (institution): Eisai Co. Ltd.; Research grant / Funding (institution): Parexel International Corp.; Research grant / Funding (institution): Kissei Pharmaceutical Co. Ltd.; Research grant / Funding (institution): IQVIA; Research grant / Funding (institution): Kyowa Hakko Kirin Co. Ltd; Research grant / Funding (institution): EPS Corporation; Research grant / Funding (institution): SymBio Pharmaceuticals Limited; Research grant / Funding (institution): Bayer Yakuhin, Ltd; Research grant / Funding (institution): Merck Serono Co. Ltd.; Research grant / Funding (institution): A2 Healthcare Corp.; Research grant / Funding (institution): AbbVie Inc.. S. Niho: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self): Chugai; Honoraria (self): Taiho; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Eli Lilly; Honoraria (self): Novartis; Honoraria (self): Boehringer Ingelheim; Research grant / Funding (institution): Merck Serono. R. Linke: Full / Part-time employment: SFJ Pharmaceuticals®. C.H. Wong: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. Y. Tang: Full / Part-time employment: Pfizer Inc. M. Singh: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. K.D. Wilner: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc. Y-L. Wu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): MSD; Honoraria (self): BMS. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background In AURA3 (NCT02151981), osimertinib, a 3rd-generation EGFR-TKI, significantly prolonged progressionfree survival (PFS) and improved response rate vs plt-pem in pts with centrally confirmed EGFR T790M advanced NSCLC and progression on a prior EGFR-TKI. Here we report mature OS data. Methods Adult pts were randomised 2:1 to receive oral osimertinib (80 mg once daily) or intravenous pem (500 mg per m2 of body surface area) + carboplatin (target area under the curve 5)/cisplatin (75 mg per m2), every 3 weeks, ≤6 cycles. Treatment beyond progression (RECIST 1.1) was allowed if clinical benefit continued. Pts receiving plt-pem could cross over to osimertinib on disease progression. Asymptomatic CNS metastases were allowed. Primary endpoint was investigator-assessed PFS. OS and safety are reported as secondary endpoints. Data cut-off (DCO): 15 March 2019. Results In total, 419 pts were randomised (osimertinib, n = 279; plt-pem, n = 140); 99 pts (71%) crossed over to osimertinib from plt-pem. At DCO, 188 pts (67%) in the osimertinib arm vs 93 pts (66%) in the plt-pem arm had died, including 66/99 (67%) crossover pts; median OS 26.8 mo (95% confidence interval [CI] 23.5, 31.5) vs 22.5 mo (95% CI 20.2, 28.8) respectively, hazard ratio (HR) 0.87 (95% CI 0.67, 1.12; p = 0.277); survival rate at 24 mo was 55% vs 43% and at 36 mo was 37% vs 30%. Time to first subsequent treatment showed a large, clinically meaningful numerical advantage towards osimertinib, HR 0.21 (95% CI 0.16, 0.28; p < 0.001); time to second subsequent treatment, HR 0.87 (95% CI 0.69, 1.11; p = 0.263). In both arms, 99% pts had any adverse event (AE). Any AE grade ≥3 causally related to study treatment was 9% vs 34% for osimertinib and plt-pem respectively. Most common AEs were diarrhoea, 44% (grade ≥3, 1%), and nausea, 49% (grade ≥3, 4%), with osimertinib and plt-pem respectively. Conclusions A numerical advantage in OS was observed for pts receiving osimertinib vs plt-pem, with the majority of pts in the plt-pem arm having crossed over to osimertinib. The safety profile of osimertinib remains consistent with previous findings. Clinical trial identification NCT02151981. Editorial acknowledgement Laura Crocker, BMedSci, of iMed Comms, an Ashfield Company, who provided medical writing support funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure Y-L. Wu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): MSD; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. T.S.K. Mok: Honoraria (self): ACEA Pharma, Alpha Biopharma Co. Ltd. Amgen, Amoy Diagnostics Co. LTD. AstraZeneca (before 1/1/19), Bayer, BI, Blueprint Medicines Corporation, BMS, Celgene, CStone Pharmaceuticals, Eli Lilly, Fishawack Facilitate Ltd, Hengrui Therapeutics Inc. Ignyt; Advisory / Consultancy: ACEA Pharma, Alpha Biopharma Co. Ltd. Amgen, Amoy Diagnostics Co. LTD. AstraZeneca (before 1/1/19), Bayer, BI, Blueprint Medicines Corporation, BMS, Celgene, Cirina, CStone Pharmaceuticals, Eli Lilly, Fishawack Facilitate Ltd, geneDecode Co. Ltd. (un; Leadership role: AstraZeneca PLC, Hutchison Chi-Med; Research grant / Funding (institution): AstraZeneca, BMS, Clovis Oncology, MSD, Novartis, Pfizer, Roche, SFJ, XCovery; Shareholder / Stockholder / Stock options: Shareholder: Hutchison Chi-Med, Sanomics Ltd. Stock option: Clearbridge Biomedics (now Biolidics Ltd.), Loxo-Oncology, OrigiMed Co. Ltd. Virtus Medical Group; Full / Part-time employment: The Chinese University of Hong Kong; Officer / Board of Directors: Remunerated: AstraZeneca PLC, Hutchison Chi-Med Non-remunerated: American Society of Clinical Oncology (ASCO) Asian Thoracic Oncology Research Group (ATORG) Chinese Lung Cancer Research Foundation Limited (CLCRF) Chinese Society of Clinical Oncology (CS. J-Y. Han: Honoraria (self): Roche, AstraZeneca, Bristol-Myers Squibb, MSD, Takeda; Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, MSD, Takeda, Pfizer, Novartis, Lilly; Research grant / Funding (self): Roche, Pfizer, Ono Pharmaceutical, Takeda. M-J. Ahn: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca, Merck, Sharp & Dohme, Ono Pharmaceutical, Lilly, Roche; Advisory / Consultancy: Alpha Pharmaceutical, Takeda. S.S. Ramalingam: Honoraria (self), Advisory / Consultancy: AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Roche/Genentech, Loxo, Nektar, Tesaro; Research grant / Funding (institution): AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Tesaro, Advaxis, Takeda. S-W. Kim: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. F.A. Shepherd: Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: AstraZeneca. J. Laskin: Research grant / Funding (institution): AstraZeneca, Roche, Boehringer Ingelheim, Pfizer; Honoraria (self): AstraZeneca, Roche, Pfizer. H. Akamatsu: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Honoraria (institution): Chugai; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Pfizer; Honoraria (self), Honoraria (institution): Boehringer Ingelheim. W-C. Su: Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Boehringer Ingelheim. T. John: Advisory / Consultancy: Roche, Bristol-Myers Squibb, Merck, Ignyta, AstraZeneca, Takeda, Boehringer Ingelheim, Pfizer. M. Sebastian: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca, Roche, Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer, Boehringer Ingelheim, Celgene, Takeda, Bristol-Myers Squibb, MSD; Honoraria (self), Advisory / Consultancy: Lilly. H. Mann: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. M. Miranda: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. G. Laus: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. Y. Rukazenkov: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. V. Papadimitrakopoulou: Honoraria (self): F Hoffman-La Roche; Advisory / Consultancy: Nektar Therapeutics, AstraZeneca Pharmaceuticals, Arrys Therapeutics, Merck&Co, LOXO Oncology, Araxes Pharma, F.Hoffman-LaRoche Ltd, Janssen Research Foundation, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly &Co, Novartis Pharmaceuticals Corp. Takeda ; Research grant / Funding (institution): Eli Lilly &Co, Novartis, Merck, AstraZeneca Pharmaceuticals, F Hoffman-La Roche, Nektar Therapeutics, Janssen, Bristol-Myers Squibb, Checkmate, Incyte. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background There is an expanding list of therapeutically relevant biomarkers for NSCLC and effective molecular profiling is paramount. We sought to comprehensively and prospectively evaluate the molecular epidemiology of NSCLC in Asia and ascertain the extent of access to relevant therapies. The study is being conducted by the Asian Thoracic Oncology Research Group (ATORG) – an academic co-operative lung cancer trials group in Asia. Methods ATORG-001 is a prospective, multi-centre study of NSCLC patients (pts) throughout Asia. Eligible pts must have good performance status (ECOG ≤2), adequate organ function and ≤3 prior lines of cytotoxic chemotherapy. Archival tissue specimens are sent to a central laboratory in Singapore (Singapore General Hospital) for profiling, consisting of NGS with the Oncomine Focus Assay (52 gene panel including fusions) and PD-L1 immunohistochemistry. Results are returned to investigators in a clinically relevant timeframe. Baseline demographics, pre-existing molecular profile and prior treatment details are collected. Treatment and pt outcomes are followed for 2 years. Recruitment commenced in Jan 2019 in 3 sites (National Cancer Centre Singapore, Chinese University of Hong Kong, University Malaya Medical Centre). We report an interim analysis for the first 27 of a planned 500 pts. Results As of 01 Jul 2019, 27 pts have enrolled with median age 67 yrs (range 46-79), 59% male, 81% adenocarcinoma, 52% stage IV, 37% non-smokers, median lines of prior therapy 1 (range 0-6) and 85% with no known oncogenic driver. Pre-existing mutation status was known in 89% for EGFR and 63% for ALK. Median turnaround time from tissue acquisition to profiling results was 22 days (range 15-74). New alterations were most common in KRAS (19%), MYC (15%), CDK4 (7%) and ERBB2 (7%). Potentially actionable new alterations were found in 7 (26%) pts, including KRAS G12C mutation (7%), BRAF G469A mutation (4%), ERBB2 exon 20 insertion (4%), ERBB2 amplification (4%), FGFR2 amplification (4%) and MET exon 14 skipping mutation (4%). Conclusions Enrolment is ongoing with additional sites and countries planned to comprehensively evaluate the molecular epidemiology of NSCLC in Asia. Legal entity responsible for the study Asian Thoracic Oncology Research Group. Funding Asian Thoracic Oncology Research Group, Novartis. Disclosure A.C. Tan: Travel / Accommodation / Expenses: ASLAN Pharmaceuticals. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background: We evaluated whether tissue tumor mutational burden (tTMB) and STK11, KEAP1, and KRAS mutations have clinical utility as biomarkers for pembrolizumab monotherapy versus platinum-based chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the phase III KEYNOTE-042 trial., Patients and Methods: This retrospective exploratory analysis assessed prevalence of tTMB and STK11, KEAP1, and KRAS mutations determined by whole-exome sequencing of tumor tissue and matched normal DNA and their associations with outcomes in KEYNOTE-042. Clinical utility of tTMB was assessed using a prespecified cut point of 175 mutations/exome., Results: Of 793 patients, 345 (43.5%) had tTMB ≥175 mutations/exome and 448 (56.5%) had tTMB <175 mutations/exome. No association was observed between PD-L1 expression and tTMB. Continuous tTMB score was associated with improved overall survival (OS) and progression-free survival among patients receiving pembrolizumab (Wald test, one-sided P < 0.001) but not those receiving chemotherapy (Wald test, two-sided P > 0.05). tTMB ≥175 mutations/exome was associated with improved outcomes for pembrolizumab versus chemotherapy, whereas tTMB <175 mutations/exome was not {OS: hazard ratio, 0.62 [95% confidence interval (CI) 0.48-0.80] and 1.09 (95% CI 0.88-1.36); progression-free survival: 0.75 (0.59-0.95) and 1.27 (1.04-1.55), respectively}. Improved OS [hazard ratio (95% CI)] for pembrolizumab versus chemotherapy was observed regardless of STK11 [STK11 mutant (n = 33): 0.37 (0.16-0.86), STK11 wild-type (n = 396): 0.83 (0.65-1.05)]; KEAP1 [KEAP1 mutant (n = 64): 0.75 (0.42-1.35), KEAP1 wild-type (n = 365): 0.78 (0.61-0.99)], or KRAS [KRAS mutant (n = 69): 0.42 (0.22-0.81); KRAS wild-type (n = 232): 0.86 (0.63-1.18)] mutation status., Conclusion: tTMB with a cut point of ≥175 mutations/exome is a potential predictive biomarker for pembrolizumab monotherapy for advanced/metastatic PD-L1 tumor proportion score ≥1% NSCLC. Pembrolizumab is a standard first-line treatment in this setting regardless of STK11, KEAP1, or KRAS mutation status., (Copyright © 2023 Merck Sharp & Dohme LLC., a subsidiary Merck & Co., Inc., The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Adenosquamous carcinoma (ASC) of the lung is a heterogeneous disease that is composed of both adenocarcinoma components (ACC) and squamous cell carcinoma components (SCCC). Their genomic profile, genetic origin, and clinical management remain controversial., Patients and Methods: Resected ASC and metastatic tumor in regional lymph nodes (LNs) were collected. The ACC and SCCC were separated by microdissection of primary tumor. The 1021 cancer-related genes were evaluated by next-generation sequencing independently in ACC and SCCC and LNs. Shared and private alterations in the two components were investigated. In addition, genomic profiles of independent cohorts of adenocarcinomas and squamous cell carcinomas were examined for comparison. We have also carried out a retrospective study of ASCs with known EGFR mutation status from 11 hospitals in China for their clinical outcomes., Results: The most frequent alterations in 28 surgically resected ASCs include EGFR (79%), TP53 (68%), MAP3K1 (14%) mutations, EGFR amplifications (32%), and MDM2 amplifications (18%). Twenty-seven patients (96%) had shared variations between ACC and SCCC, and pure SCCC metastases were not found in metastatic LNs among these patients. Only one patient with geographically separated ACC and SCCC had no shared mutations. Inter-component heterogeneity was a common genetic event of ACC and SCCC. The genomic profile of ASC was similar to that of 170 adenocarcinomas, but different from that of 62 squamous cell carcinomas. The incidence of EGFR mutations in the retrospective analysis of 517 ASCs was 51.8%. Among the 129 EGFR-positive patients who received EGFR-TKIs, the objective response rate was 56.6% and the median progression-free survival was 10.1 months (95% confidence interval: 9.0-11.2)., Conclusions: The ACC and SCCC share a monoclonal origin, a majority with genetically inter-component heterogeneity. ASC may represent a subtype of adenocarcinoma with EGFR mutation being the most common genomic anomaly and sharing similar efficacy to EGFR TKI., Competing Interests: Disclosure TSKM reports grants and personal fees from AstraZeneca, Roche/Genentech, Bristol-Myers Squibb, Boehringer Ingelheim, Novartis, Merck Sharp and Dohme, Pfizer, SFJ Pharmaceuticals, Clovis Oncology, and Taiho; personal fees from Eli Lilly, Merck Serono, Vertex, ACEA Biosciences, Oncogenex, Celgene, and Ignyta; an uncompensated relationship with geneDecode and Cirina; grants from Eisai; and ownership of stock in Samomics Ltd. The remaining authors declare no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Lung cancer is a common cancer associated with high mortality rates worldwide. Unfortunately, it usually presents at a late stage, precluding the chance of curative therapy. The discovery of oncogenic driver mutations in patients with non-small cell lung cancer over the past 20 years has led to new molecular targeted therapies that have dramatically improved treatment efficacy and quality of life. New generations of therapy that target the drug-resistant mutations have also quickly evolved, benefiting patients who are refractory or intolerant to first-line targeted therapy. Eastern patients, from Southeast Asia, Japan and China, are known to have a higher incidence of epidermal growth factor receptor mutation. Therefore, compared with the West, more patients would benefit from these recent advances. In contrast, survival of patients without driver mutations has benefited from advances in novel therapeutics, including the immune checkpoint inhibitors. The current review aims to highlight the recent developments in the management of advanced-stage non-small cell lung cancer and to compare the differences in clinical practice between Eastern and Western countries., (Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Aims: Almost all patients with epidermal growth factor receptor (EGFR) mutations will develop resistance to first-line EGFR tyrosine kinase inhibitors (TKIs). The management of oligoprogression on EGFR TKI is controversial. Irradiating progressing tumours may potentially eradicate the resistant clone and allow continuation of EGFR TKI, but the clinical data remain sparse. We aimed to assess the effect of radiotherapy on survival outcomes in patients with oligoprogression in a matched-cohort study., Materials and Methods: This was a retrospective matched-cohort study comparing patients with EGFR mutation-positive stage IV non-small cell lung cancer receiving radiotherapy versus chemotherapy for progression. Patients in the radiotherapy group received radiotherapy (mainly stereotactic ablative radiotherapy) for oligoprogression, whereas the chemotherapy group received only systemic chemotherapy upon progression. Key prognostic factors including gender, age, performance status, time to first progression and mutation subtypes were matched., Results: Twenty-five patients with oligoprogression (radiotherapy group) were identified, and a matched chemotherapy group with the same number of patients was generated. The median duration of follow-up was 24.3 and 34 months for the radiotherapy and chemotherapy groups, respectively. The median overall survival of the radiotherapy group was significantly longer than the chemotherapy group, 28.2 versus 14.7 months (P = 0.026). The median progression-free survival (PFS) was 7.0 and 4.1 months after radiotherapy and chemotherapy, respectively (P = 0.0017). The use of radiotherapy was an independent predictive factor of overall survival and PFS in multivariate analysis. Only one patient had ≥grade 3 toxicity after radiotherapy. The frequency of secondary T790M mutation and subsequent Osimertinib exposure were similar in both groups., Conclusion: Radiotherapy may effectively extend EGFR TKI therapy for patients with oligoprogression on TKI. Improved PFS and overall survival were observed, although potential biases should not be overlooked. Further randomised studies are warranted., (Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Squamous cell carcinoma (SqC) and adenocarcinoma (AdC) are the two most common subtypes of non-small cell lung cancer (NSCLC). Cumulative information suggests that the SqC and AdC subtypes progress through different carcinogenic pathways, but the genetic aberrations promoting such differences remain unclear. Here we have assessed the overall genomic imbalances and structural abnormalities in SqC and AdC. By parallel analyses with comparative genomic hybridisation (CGH) on tumorous lung tissues and spectral karyotyping (SKY) on short-term cultured primary tumours, genome-wide characterisation was carried out on 69 NSCLC (35 SqC, 34 AdC). Molecular cytogenetic characterisation indicated common and distinct genetic changes in SqC and AdC. Common events of +1q21-q24, +5p15-p14, and +8q22-q24.1, and -17p13-p12 were found in both groups, although hierarchical clustering simulation on CGH findings depicted +2p13-p11.2, +3q25-q29, +9q13-q34, +12p, +12q12-q15 and +17q21, and -8p in preferential association with SqC pathogenesis (P<0.05). Corresponding SKY analysis suggested that these changes occur in simple and complex rearrangements, and further indicated the clonal presence of translocation partners leading to chromosomal over-representations. These recurring rearrangements involved chromosome pairs of t(1;13), t(1;15), t(7;8), t(8;15), t(8;9), t(2;17) and t(15;20). Of particular interest was the finding that the t(8;12) translocation partner was exclusive to AdC. The combined application of SKY and CGH has thus uncovered the genome-wide chromosomal aberrations in NSCLC. Specific chromosomal imbalances and translocation partners found in SqC and AdC have highlighted regions for further molecular investigation into gene(s) that may hold importance in the carcinogenesis of NSCLC.

This descriptive study aimed to evaluate the antiemetic protection of metoclopramide plus dexamethasone in a sample of 33 Chinese breast cancer patients who were receiving doxorubicin and cyclophosphamide. The antiemetic protection effect was not satisfactory. The results showed that the worst nausea and vomiting was experienced on the third day, with 87.9% of patients reporting nausea and 63.6% experiencing vomiting on that day. In almost one-third of the sample antiemetic medication failed to protect against either acute vomiting or delayed vomiting (i.e. patients continued to experience more than five emetic episodes). Complete protection from acute vomiting was seen in 36.4% of patients, whereas complete protection from delayed vomiting was seen in only one-third of the patients. There was an association between acute nausea/vomiting and delayed nausea/vomiting. Different types of antiemetics need to be offered to Chinese patients receiving chemotherapy (i.e. 5-HT3 receptor antagonists or a combination of antiemetics), but more research should be directed to this area.

This study was a randomised controlled trial designed to assess the effectiveness of progressive muscle relaxation training (PMRT) in the clinical management of chemotherapy-related nausea and vomiting as an adjuvant intervention to accompany pharmacological antiemetic treatment (metoclopramide and dexamethasone i.v.). Seventy-one chemotherapy-naive breast cancer patients of an outpatient oncology unit of a university hospital in Hong Kong participated, with 38 subjects randomised to the experimental group and 33 to the control group. The intervention included the use of PMRT 1 h before chemotherapy was administered and daily thereafter for another 5 days (for a total of six PMRT sessions). Each session lasted for 25 min and was followed by 5 min of imagery techniques. The instruments used for data collection included the Chinese versions of the Profile of Mood States and the State-Trait Anxiety Inventory (measured before chemotherapy and then at day 7 and day 14 after chemotherapy), and the Morrow Assessment of Nausea and Vomiting Scale, which was used daily for the first 7 post-chemotherapy days. The use of PMRT considerably decreased the duration of nausea and vomiting in the experimental group compared with the control group ( P<0.05), whereas there were trends toward a lower frequency of nausea and vomiting ( P=0.07 and P=0.08 respectively). Neither nausea nor vomiting differed in intensity between the two groups. The significant effects were mainly evident on the first 4 post-chemotherapy days, when differences were statistically significant. Although there was a significantly less severe overall mood disturbance in the experimental group over time ( P<0.05), this did not apply in the case of anxiety. Such findings suggest that PMRT is a useful adjuvant technique to complement antiemetics for chemotherapy-induced nausea and vomiting and that incorporation of such interventions in the care plan can enhance the standards of care of cancer patients who experience side effects of chemotherapy.