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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. 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. 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. 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. • Pembrolizumab monotherapy is a standard first-line treatment of patients with PD-L1-positive advanced/metastatic NSCLC. • We assessed clinical utility of potential biomarkers among patients receiving pembrolizumab versus chemotherapy. • tTMB ≥175 mutations/exome was associated with improved outcomes among patients receiving pembrolizumab versus chemotherapy. • tTMB has potential clinical utility as a biomarker for pembrolizumab in first-line PD-L1-positive advanced/metastatic NSCLC. • Pembrolizumab improved overall survival versus chemotherapy regardless of STK11 , KEAP1 , or KRAS mutation status. [ABSTRACT FROM AUTHOR]

In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis. Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum–pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points. A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum–pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum–pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67–1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5–31.5) versus 22.5 months (95% CI 20.2–28.8) for osimertinib and platinum–pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18–1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16–0.28; P < 0.001). At DCO, 99/136 (73%) patients in the platinum–pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3, <1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum–pemetrexed arm. In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum–pemetrexed, which possibly reflects the high crossover rate of patients from platinum–pemetrexed to osimertinib. ClinicalTrials.gov NCT02151981 ; https://clinicaltrials.gov/ct2/show/NCT02151981. • Median OS with osimertinib was 26.8 months versus 22.5 months with platinum–pemetrexed (HR 0.87, 95% CI 0.67–1.12; P = 0.277). • The lack of a significant survival benefit could reflect high percentage (73%) of platinum–pemetrexed to osimertinib crossover. • Analysis of OS adjusted for crossover showed an HR of 0.54 (95% CI 0.18–1.60). • Among patients receiving subsequent anticancer therapy, platinum chemotherapy was the most common after osimertinib (65%). • Grade ≥3 (possibly treatment-related) adverse events were observed less frequently with osimertinib (9% versus 34% with platinum–pemetrexed). [ABSTRACT FROM AUTHOR]

Background: The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019). Patients and methods: Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety. Results: Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32e0.58; median PFS 34.8 versus 10.9 months crizotinib]. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with crizotinib (stratified HR 0.67, 95% CI 0.46e0.98). The 5-year OS rate was 62.5% (95% CI 54.3e70.8) with alectinib and 45.5% (95% CI 33.6e57.4) with crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline [HR 0.58 (95% CI 0.34e1.00)] and those without [HR 0.76 (95% CI 0.45 e1.26)]. Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed. Conclusions: Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over crizotinib in ALKpositive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus crizotinib in treatment-naive ALK-positive NSCLC. [ABSTRACT FROM AUTHOR]

A phase II study investigating intercalated combinations of eribulin and erlotinib in 21- and 28-day regimens in unselected patients with previously treated advanced non-small-cell lung cancer. Combination treatment demonstrated modest activity; the addition of erlotinib did not appear to improve outcomes in an unselected population. The 28-day regimen is suitable for further investigation.Background This phase II, open-label study investigated intercalated combinations of eribulin and erlotinib in unselected patients with advanced non-small-cell lung cancer previously treated with platinum-based chemotherapies. Patients and methods Eligible patients were randomized to eribulin mesylate 2.0 mg/m2 on day 1 with erlotinib 150 mg on days 2–16 (21-day regimen) or eribulin mesylate 1.4 mg/m2 on days 1 and 8 with erlotinib 150 mg on days 15–28 (28-day regimen). The primary end point was objective response rate (ORR). Results One hundred and twenty-three patients received ≥1 cycle of therapy (63, 21-day regimen; 60, 28-day regimen). ORRs were 13% [95% confidence interval (CI) 6%–24%] and 17% (95% CI 8%–29%), and disease control rates were 48% (95% CI 35%–61%) and 63% (95% CI 50%–75%) for the 21- and 28-day regimens, respectively. The median progression-free survival and overall survival were similar with both regimens. Both regimens were well tolerated with common grade ≥3 toxicities being neutropenia, asthenia/fatigue, and dyspnoea. Sequential administration of erlotinib did not interfere with the pharmacokinetic profile of eribulin. Conclusion Intercalated combination of eribulin and erlotinib demonstrated modest activity and the addition of erlotinib did not appear to improve treatment outcome in an unselected population. The 28-day regimen is suitable for further investigation. Clinicaltrials.gov identifier NCT01104155. [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 The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK +) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX. Patients and methods Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression. Results In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib, n  =   64; crizotinib, n  =   58), 43 had measurable lesions (alectinib, n  =   21; crizotinib, n  =   22), and 46 had received prior radiotherapy (alectinib, n  =   25; crizotinib, n  =   21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25–0.64] and those without (HR 0.51, 95% CI: 0.33–0.80, P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus crizotinib and comparable between patients with and without baseline CNS metastases (P  <   0.0001). CNS ORR was 85.7% with alectinib versus 71.4% with crizotinib in patients who received prior radiotherapy and 78.6% versus 40.0%, respectively, in those who had not. Conclusion Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advanced ALK + NSCLC, irrespective of prior CNS disease or radiotherapy. Clinical trial registration ClinicalTrials.gov NCT02075840 [ABSTRACT FROM AUTHOR]

Front-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) therapy is the standard of care for lung cancer patients with sensitising EGFR mutations (exon 19 deletion or L858R mutation). Several phase III studies have demonstrated the superiority of gefitinib, erlotinib (first generation of TKIs) or afatinib (second generation) to chemotherapy in progression-free survival and response rates. Drug-related toxicities, such as diarrhoea, acneiform skin rash, mucositis, and paronychia, are frequently encountered in patients who receive EGFR TKIs. Other rare side-effects, such as hepatic impairment and interstitial lung disease, should be identified early and managed carefully. Patients with uncommon EGFR mutations, such as G719X, S768I, and L861Q, may require special selection of EGFR TKIs. The combination of erlotinib plus bevacizumab has been accepted in certain parts of the world as an alternative front-line treatment. This review article summarizes the studies leading to the establishment of EGFR TKIs in EGFR-mutant lung cancer patients. The side-effect profiles of the current EGFR TKIs in these large trials are listed, and the management of uncommon EGFR mutations is discussed. Finally, the potential role of combination front-line treatment is discussed. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy remains a viable option for the management of advanced non-small-cell lung cancer (NSCLC) despite recent advances in molecular targeted therapy and immunotherapy. We evaluated the efficacy of oral 5-fluorouracil-based S-1 as second- or third-line therapy compared with standard docetaxel therapy in patients with advanced NSCLC. Patients and methods: Patients with advanced NSCLC previously treated with ≥ 1 platinum-based therapy were randomized 1 : 1 to docetaxel (60 mg/m² in Japan, 75 mg/m² at all other study sites; day 1 in a 3-week cycle) or S-1 (80-120 mg/day, depending on body surface area; days 1-28 in a 6-week cycle). The primary endpoint was overall survival. The non-inferiority margin was a hazard ratio (HR) of 1.2. Results: A total of 1154 patients (577 in each arm) were enrolled, with balanced patient characteristics between the two arms. Median overall survival was 12.75 and 12.52 months in the S-1 and docetaxel arms, respectively [HR 0.945; 95% confidence interval (CI) 0.833-1.073; P=0.3818]. The upper limit of 95% CI of HR fell below 1.2, confirming non-inferiority of S-1 to docetaxel. Difference in progression-free survival between treatments was not significant (HR 1.033; 95% CI 0.913-1.168; P=0.6080). Response rate was 8.3% and 9.9% in the S-1 and docetaxel arms, respectively. Significant improvement was observed in the EORTC QLQ-C30 global health status over time points in the S-1 arm. The most common adverse drug reactions were decreased appetite (50.4%), nausea (36.4%), and diarrhea (35.9%) in the S-1 arm, and neutropenia (54.8%), leukocytopenia (43.9%), and alopecia (46.6%) in the docetaxel arm. Conclusion: S-1 is equally as efficacious as docetaxel and offers a treatment option for patients with previously treated advanced NSCLC. [ABSTRACT FROM AUTHOR]

• This ESMO Clinical Practice Guideline provides key recommendations and algorithms for managing oncogene-addicted mNSCLC. • ESMO-MCBS scores are given to describe the levels of evidence for treatment choices. • ESCAT scores are given to describe the evidence level for genomic alterations as biomarkers for using targeted therapies. • Recommendations are based on available scientific data and the authors' collective expert opinion. • In clinical practice, all recommendations provided need to be discussed with patients in a shared decision-making approach. [ABSTRACT FROM AUTHOR]

• This ESMO Clinical Practice Guideline provides key recommendations and algorithms for managing non-oncogene-addicted mNSCLC. • ESMO-MCBS scores are given to describe the levels of evidence for treatment choices. • ESCAT scores are given to describe the evidence level for genomic alterations as biomarkers for using targeted therapies. • Recommendations are based on available scientific data and the authors' collective expert opinion. • In clinical practice, all recommendations provided need to be discussed with patients in a shared decision-making approach. [ABSTRACT FROM AUTHOR]

Background: Chinese herbal medicine (CHM) is a common complementary therapy used by patients with cancer for reduction of chemotherapy-induced toxic effects. This study applied the highest standard of clinical trial methodology to examine the role of CHM in reducing chemotherapy-induced toxicity, while maintaining a tailored approach to therapy. Patients and methods: Patients with early-stage breast or colon cancer who required postoperative adjuvant chemotherapy were eligible for the study. Enrolled patients were randomly assigned to one of three Chinese herbalists who evaluated and prescribed a combination of single-item packaged herbal extract granules. Patients received either CHM or placebo packages with a corresponding serial number. The placebo package contained nontherapeutic herbs with an artificial smell and taste similar to a typical herbal tea. The primary end points were hematologic and non-hematologic toxicity according to the National Cancer Institute Common Toxicity Criteria Version 2. Results: One hundred and twenty patients were accrued at the time of premature study termination. Patient characteristics of the two groups were similar. The incidence of grade 3/4 anemia, leukopenia, neutropenia, and thrombocytopenia for the CHM and placebo groups were 5.4%, 47.3%, 52.7%, and 1.8% and 1.8%, 32.2%, 44.7%, and 3.6%, respectively (P = 0.27, 0.37, 0.63, and 0.13, respectively). Incidence of grade 2 nausea was the only non-hematologic toxicity that was significantly reduced in the CHM group (14.6% versus 35.7%, P = 0.04). Conclusions: Traditional CHM does not reduce the hematologic toxicity associated with chemotherapy. CHM, however, does have a significant impact on control of nausea. [ABSTRACT FROM AUTHOR]

Acquired resistance (AR) to programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] blockade is frequent in non-small-cell lung cancer (NSCLC), occurring in a majority of initial responders. Patients with AR may have unique properties of persistent antitumor immunity that could be re-harnessed by investigational immunotherapies. The absence of a consistent clinical definition of AR to PD-(L)1 blockade and lack of uniform criteria for ensuing enrollment in clinical trials remains a major barrier to progress; such clinical definitions have advanced biologic and therapeutic discovery. We examine the considerations and potential controversies in developing a patient-level definition of AR in NSCLC treated with PD-(L)1 blockade. Taking into account the specifics of NSCLC biology and corresponding treatment strategies, we propose a practical, clinical definition of AR to PD-(L)1 blockade for use in clinical reports and prospective clinical trials. Patients should meet the following criteria: received treatment that includes PD-(L)1 blockade; experienced objective response on PD-(L)1 blockade (inclusion of a subset of stable disease will require future investigation); have progressive disease occurring within 6 months of last anti-PD-(L)1 antibody treatment or rechallenge with anti-PD-(L)1 antibody in patients not exposed to anti-PD-(L)1 in 6 months. • In NSCLC, acquired resistance to immunotherapy is common and poorly understood. • A uniform clinical definition is imperative to further characterize patients and develop a rational approach to overcoming acquired resistance. • The proposed definition seeks to unify language for future reports and clinical trials in NSCLC. • We also highlight specific areas of uncertainty in classification of acquired resistance that require urgent attention and could lead to further refinements in the future. [ABSTRACT FROM AUTHOR]

Background In clinical trials of patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) treated with crizotinib, evaluation of the relationship between the percentage of ALK-positive cells by fluorescence in situ hybridization (FISH)—particularly near the cut-off defining positive status—and clinical outcomes have been limited by small sample sizes. Patients and methods Data were pooled from three large prospective trials (one single-arm and two randomized versus chemotherapy) of crizotinib in patients with ALK-positive NSCLC determined by Vysis ALK Break Apart FISH using a cut-off of ≥15% ALK-positive cells. Logistic regression and proportional hazards regression analyses were used to explore the association of percent ALK-positive cells with objective response and progression-free survival (PFS), respectively. Results Of 11 081 screened patients, 1958 (18%) were ALK positive, 7512 (68%) were ALK negative, and 1540 (14%) were uninformative. Median percentage of ALK-positive cells was 58% in ALK-positive patients and 2% in ALK-negative patients. Of ALK-positive patients, 5% had 15%–19% ALK-positive cells; of ALK-negative patients, 2% had 10%–14% ALK-positive cells. Objective response rate for ALK-positive, crizotinib-treated patients with ≥20% ALK-positive cells was 56% (n  =   700/1246), 55% (n  =   725/1312) for those with ≥15% ALK-positive cells, and 38% for those with 15%–19% ALK-positive cells (n  =   25/66). As a continuous variable, higher percentages of ALK-positive cells were estimated to be associated with larger differences in objective response and PFS between crizotinib and chemotherapy; however, tests for interaction between treatment and percentage of ALK-positive cells were not significant (objective response, P  =   0.054; PFS, P  =   0.17). Conclusions Patients with ALK-positive NSCLC benefit from treatment with crizotinib across the full range of percentage of ALK-positive cells, supporting the clinical utility of the 15% cut-off. The small number of patients with scores near the cut-off warrant additional study given the potential for misclassification of ALK status due to technical or biologic reasons. [ABSTRACT FROM AUTHOR]

Background: In LUX-Lung 7, the irreversible ErbB family blocker, afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus gefitinib in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data. Patients and methods: LUX-Lung 7 assessed afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naïve patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R). Primary OS analysis was planned after ~213 OS events and&#880532-month follow-up. OS was analysed by a Cox proportional hazards model, stratified by EGFR mutation type and baseline brain metastases. Results: Two-hundred and twenty-six OS events had occurred at the data cut-off (8 April 2016). After a median follow-up of 42.6 months, median OS (afatinib versus gefitinib) was 27.9 versus 24.5 months [hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.66-1.12, P=0.2580]. Prespecified subgroup analyses showed similar OS trends (afatinib versus gefitinib) in patients with exon 19 deletion (30.7 versus 26.4 months; HR, 0.83, 95% CI 0.58-1.17, P=0.2841) and L858R (25.0 versus 21.2 months; HR 0.91, 95% CI 0.62-1.36, P=0.6585) mutations. Most patients (afatinib, 72.6%; gefitinib, 76.8%) had at least one subsequent systemic anti-cancer treatment following discontinuation of afatinib/gefitinib; 20 (13.7%) and 23 (15.2%) patients received a thirdgeneration EGFR tyrosine kinase inhibitor. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib. Conclusion: In LUX-Lung 7, there was no significant difference in OS with afatinib versus gefitinib. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib. [ABSTRACT FROM AUTHOR]

Background: Afatinib 40 mg/day is approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). In the case of drug-related grade =3 or selected prolonged grade 2 adverse events (AEs), the dose can be reduced by 10 mg decrements to a minimum of 20 mg. Here, we evaluate the influence of afatinib dose reduction on AEs, pharmacokinetics and progression-free survival (PFS) in the phase III LUX-Lung 3 and 6 (LL3/6) trials. Patients and methods: Treatment-naïve patients with advanced EGFR mutation-positive NSCLC in LL3 (global) and LL6 (China, Thailand, South Korea) were randomized to afatinib or chemotherapy. All afatinib-treated patients (LL3, n = 229; LL6, n = 239) were included in the post hoc analyses. Incidence and severity of common AEs before and after afatinib dose reduction were assessed. Afatinib plasma concentrations were compared in patients who reduced to 30 mg versus those remaining at 40 mg. PFS was compared between patients who dose reduced within the first 6 months of treatment and those who did not. Results: Dose reductions occurred in 53.3% (122/229) and 28.0% (67/239) of patients in LL3 and LL6, respectively; most (86.1% and 82.1%) within the first 6 months of treatment. Dose reduction led to decreases in the incidence of drug-related AEs, and was more likely in patients with higher afatinib plasma concentrations. On day 43, patients who dose reduced to 30 mg (n = 59) had geometric mean afatinib plasma concentrations of 23.3 ng/ml, versus 22.8 ng/ml in patients who remained on 40 mg (n = 284). The median PFS was similar in patients who dose reduced during the first 6 months versus those who did not {LL3: 11.3 versus 11.0 months [hazard ratio (HR) 1.25]; LL6: 12.3 versus 11.0 months (HR 1.00)}. Conclusions: Tolerability-guided dose adjustment is an effective measure to reduce afatinib-related AEs without affecting therapeutic efficacy. [ABSTRACT FROM AUTHOR]