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Background We conducted a feasibility study of induction chemotherapy followed by gefitinib and thoracic radiotherapy (TRT) for unresectable locally advanced adenocarcinoma of the lung. Patients and methods Patients received induction chemotherapy with cisplatin (80 mg/m2, days 1 and 22) and vinorelbine (25 mg/m2, days 1, 8, 22, and 29) followed by gefitinib (250 mg daily, beginning on day 43, for 1 year) and TRT (60 Gy/30 fractions, days 57–98). The primary end point was feasibility, which was defined as the proportion of patients who completed 60 Gy of TRT and received >75% of the planned dose of gefitinib without developing grade 2 or worse pneumonitis. Results Of the 38 enrolled patients, 23 patients [60.5% ; 80% confidence interval (CI) 48.8–71.3] completed treatment without experiencing grade 2 or worse pneumonitis. During the chemoradiation phase, grade 3–4 alanine aminotransferase elevations were observed in 37.1% of the patients. The overall response rate was 73.0% . The median survival time was 28.5 months (95% CI 22.5–38.2), and the 2-year survival rate was 65.4% . Conclusions Although the results did not meet our criterion for feasibility, the toxicity was acceptable. This treatment warrants further evaluation among patients with locally advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations. [ABSTRACT FROM PUBLISHER]

Background Osimertinib is a 3rd-generation, irreversible, oral EGFR-TKI that potently and selectively inhibits both EGFR-mutated (EGFRm) and EGFR T790M resistance mutations, and has demonstrated efficacy in NSCLC CNS metastases. In the Phase III FLAURA study (NCT02296125), osimertinib resulted in significant progression-free survival (PFS) benefit (primary endpoint; datacut off [DCO] 12 June 2017) over comparator EGFR-TKI (HR 0.46, p < 0.001). Overall survival (OS) data were immature (25% maturity) at that time. Here, we report the final OS analysis (58% maturity). Methods Eligible patients (pts): ≥18 years (Japan: ≥20), treatment-naïve with Ex19del/L858R EGFRm advanced NSCLC; WHO performance status 0–1. Pts with stable CNS metastases not requiring steroids for ≥2 weeks were allowed. Pts were randomised 1:1 to osimertinib 80 mg once daily (qd) orally (po) or comparator EGFR-TKI (gefitinib 250 mg qd/erlotinib 150 mg qd po), stratified by mutation status (Ex19del/L858R) and race (Asian/non-Asian). Crossover was allowed for pts in the comparator EGFR-TKI arm upon central confirmation of progression and T790M positivity. Primary endpoint: PFS by RECIST v1.1, per investigator. OS was a secondary endpoint. DCO 25 June 2019. Results Globally, 556 pts were randomised to osimertinib (n = 279) or comparator EGFR-TKI (n = 277). Per study protocol, 70 (25%) pts crossed over from comparator EGFR-TKI to osimertinib. Osimertinib significantly improved OS vs comparator EGFR-TKI. All causality AEs, per investigator: osimertinib, 98% (grade ≥3, 42%); comparator EGFR-TKI, 98% (grade ≥3, 47%). AEs leading to discontinuation: osimertinib, 15%; comparator EGFR-TKI, 18%. The safety profile appears consistent with previously reported data. Table: LBA16 Efficacy output  Osimertinib n = 279  Comparator EGFR-TKI n = 277  OS hazard ratio  0.799 (0.641, 0.997); p = 0.0462  (95.05% confidence interval)  Median OS, months  38.6 (34.5, 41.8)  31.8 (26.6, 36.0)  (95% confidence interval)      Deaths, total pts (%)  155 (56)  166 (60)  Median follow-up for OS in all pts, months  35.8  27.0  Median follow-up for OS in censored * pts, months  43.1  43.1  12-month survival rate, % (95% confidence interval)  89 (85, 92)  83 (77, 87)  24-month survival rate, % (95% confidence interval)  74 (69, 79)  59 (53, 65)      36-month survival rate, % (95% confidence interval)  54 (48, 60)  44 (38, 50)      Efficacy output  Osimertinib n = 279  Comparator EGFR-TKI n = 277  OS hazard ratio  0.799 (0.641, 0.997); p = 0.0462  (95.05% confidence interval)  Median OS, months  38.6 (34.5, 41.8)  31.8 (26.6, 36.0)  (95% confidence interval)      Deaths, total pts (%)  155 (56)  166 (60)  Median follow-up for OS in all pts, months  35.8  27.0  Median follow-up for OS in censored * pts, months  43.1  43.1  12-month survival rate, % (95% confidence interval)  89 (85, 92)  83 (77, 87)  24-month survival rate, % (95% confidence interval)  74 (69, 79)  59 (53, 65)      36-month survival rate, % (95% confidence interval)  54 (48, 60)  44 (38, 50)      OS for patients in the full analysis set was analysed using a log rank test (stratified by race and mutation type) for generation of the p-value and using the Breslow approach for handling ties. The median OS with 95% confidence intervals were calculated by Kaplan Meier technique. For statistical significance, a 2-sided p-value of less than 0.0495, as determined by the O'Brien-Fleming approach was required due the previous interim analysis. * Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Table: LBA16 Efficacy output  Osimertinib n = 279  Comparator EGFR-TKI n = 277  OS hazard ratio  0.799 (0.641, 0.997); p = 0.0462  (95.05% confidence interval)  Median OS, months  38.6 (34.5, 41.8)  31.8 (26.6, 36.0)  (95% confidence interval)      Deaths, total pts (%)  155 (56)  166 (60)  Median follow-up for OS in all pts, months  35.8  27.0  Median follow-up for OS in censored * pts, months  43.1  43.1  12-month survival rate, % (95% confidence interval)  89 (85, 92)  83 (77, 87)  24-month survival rate, % (95% confidence interval)  74 (69, 79)  59 (53, 65)      36-month survival rate, % (95% confidence interval)  54 (48, 60)  44 (38, 50)      Efficacy output  Osimertinib n = 279  Comparator EGFR-TKI n = 277  OS hazard ratio  0.799 (0.641, 0.997); p = 0.0462  (95.05% confidence interval)  Median OS, months  38.6 (34.5, 41.8)  31.8 (26.6, 36.0)  (95% confidence interval)      Deaths, total pts (%)  155 (56)  166 (60)  Median follow-up for OS in all pts, months  35.8  27.0  Median follow-up for OS in censored * pts, months  43.1  43.1  12-month survival rate, % (95% confidence interval)  89 (85, 92)  83 (77, 87)  24-month survival rate, % (95% confidence interval)  74 (69, 79)  59 (53, 65)      36-month survival rate, % (95% confidence interval)  54 (48, 60)  44 (38, 50)      OS for patients in the full analysis set was analysed using a log rank test (stratified by race and mutation type) for generation of the p-value and using the Breslow approach for handling ties. The median OS with 95% confidence intervals were calculated by Kaplan Meier technique. For statistical significance, a 2-sided p-value of less than 0.0495, as determined by the O'Brien-Fleming approach was required due the previous interim analysis. * Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Conclusions Osimertinib provided a statistically significant and clinically meaningful improvement in OS vs comparator EGFR-TKI in first-line pts with EGFRm advanced NSCLC. Clinical trial identification NCT02296125. Editorial acknowledgement Natalie Griffiths, PhD, from iMed Comms, an Ashfield Company, funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure B.C. Cho: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, MSD; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Licensing / Royalties: Champions Oncology; Honoraria (institution), Advisory / Consultancy: Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Eli Lilly, Takeda; Shareholder / Stockholder / Stock options: TheraCanVac Inc. Y. Ohe: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca, Chugai, Dainippon Lilly, Ono, BMS Japan, Daiichi Sankyo, BI, Bayer, Ignyta, Pfizer, MSD, Taiho, Novartis, Kyorin, Kyowa Hakko Kirin, Takeda, Celltrion, Kissei, Amgen, Janssen, Roxo. C. Zhou: Honoraria (self): Roche, Eli Lilly, BI, Merck, Hengrui, Qiru. B. Chewaskulyong: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca. D. Planchard: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, MedImmune, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Research grant / Funding (institution): AstraZeneca, Bristol-Myers Squibb, AbbVie, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, MedImmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo; Travel / Accommodation / Expenses: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim , Roche, Merck, Novartis, prIME Oncology, Pfizer. J.F. Vansteenkiste: Research grant / Funding (institution): MSD; Advisory / Consultancy: – Apotex, AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Roche; Speaker Bureau / Expert testimony: – AstraZeneca, BMS, MSD, Roche. J.E. Gray: Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Takeda; Advisory / Consultancy: Bristol-Myers Squibb, Celgene, Takeda; Research grant / Funding (institution): Array, Merck, AstraZeneca, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb. R. Shah: Honoraria (self), Travel / Accommodation / Expenses: Boehringer Ingelheim, Roche, AstraZeneca. P.K. Cheema: Honoraria (self), Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Merck, Takeda, Novartis, Genomic Health, Pfizer. M. Tiseo: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, MSD, Boehringer Ingelheim, Takeda; Research grant / Funding (institution): AstraZeneca, Boehringer Ingelheim. T. John: Advisory / Consultancy: Roche, Bristol-Myers Squibb, Merck, Ignyta, AstraZeneca, Takeda, Boehringer Ingelheim, Pfizer. R. Hodge: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. Y. Rukazenkov: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. Soria: Advisory / Consultancy: AstraZeneca, Astex, Clovis, GSK, GamaMabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, PharmaMar, Pierre Fabre, Roche/Genentech, Sanofi, Servier, Symphogen, Takeda; Shareholder / Stockholder / Stock options: AstraZeneca, Gritstone; Full / Part-time employment: AstraZeneca. F. Imamura: Honoraria (self), Research grant / Funding (institution): AstraZeneca. 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. [ABSTRACT FROM AUTHOR]

First-line nivolumab plus ipilimumab prolongs survival versus chemotherapy in advanced non-small-cell lung cancer (NSCLC). We further characterized clinical benefit with this regimen in a large pooled patient population and assessed the effect of response on survival. Data were pooled from four studies of first-line nivolumab plus ipilimumab in advanced NSCLC (CheckMate 227 Part 1, 817 cohort A, 568 Part 1, and 012). Overall survival (OS), progression-free survival (PFS), objective response rate, duration of response, and safety were assessed. Landmark analyses of OS by response status at 6 months and by tumor burden reduction in responders to nivolumab plus ipilimumab were also assessed. In the pooled population (N = 1332) with a minimum follow-up of 29.1-58.9 months, median OS was 18.6 months, with a 3-year OS rate of 35%; median PFS was 5.4 months (3-year PFS rate, 17%). Objective response rate was 36%; median duration of response was 23.7 months, with 38% of responders having an ongoing response at 3 years. In patients with tumor programmed death-ligand 1 (PD-L1) <1%, ≥1%, 1%-49%, or ≥50%, 3-year OS rates were 30%, 38%, 30%, and 48%. Three-year OS rates were 30% and 38% in patients with squamous or non-squamous histology. Efficacy outcomes in patients aged ≥75 years were similar to the overall pooled population (median OS, 20.1 months; 3-year OS rate, 34%). In the pooled population, responders to nivolumab plus ipilimumab at 6 months had longer post-landmark OS than those with stable or progressive disease; 3-year OS rates were 66%, 22%, and 14%, respectively. Greater depth of response was associated with prolonged survival; in patients with tumor burden reduction ≥80%, 50% to <80%, or 30% to <50%, 3-year OS rates were 85%, 72%, and 44%, respectively. No new safety signals were identified in the pooled population. Long-term survival benefit and durable response with nivolumab plus ipilimumab in this large patient population further support this first-line treatment option for advanced NSCLC. • Pooled analyses from four 1L NIVO + IPI studies support the durable efficacy of this regimen for advanced NSCLC treatment. • Durable responses and long-term survival benefit with NIVO + IPI were observed across histologies/PD-L1 expression levels. • Patients who had a response at 6 months with 1L NIVO + IPI had improved post-landmark survival benefit. • Responders with higher tumor burden reduction from baseline derived long-term OS benefit. [ABSTRACT FROM AUTHOR]