Abstract Background Historically, pts with NSCLC and brain metastases have had poor prognosis. Randomized studies have shown OS and PFS benefit and manageable safety with pembro plus chemo vs chemo alone in pts with advanced NSCLC. We present a pooled analysis of outcomes in pts with NSCLC and stable brain metastases at baseline who were enrolled in randomized clinical trials evaluating pembro plus platinum-based chemo as first-line therapy for advanced/metastatic NSCLC. Methods This post hoc analysis pooled data for pts with stable, treated or untreated brain metastases from KEYNOTE-021 cohort G (nonsquamous; NCT02039674), 189 (nonsquamous; NCT02578680), and 407 (squamous; NCT02775435). Pts were randomly assigned to platinum-doublet chemo (pemetrexed-carboplatin/cisplatin for nonsquamous NSCLC and carboplatin-paclitaxel/nab-paclitaxel for squamous NSCLC) with/without pembro; KEYNOTE-189 and 407 were placebo-controlled. Response (systemic, including in brain) was assessed per RECIST v1.1 by blinded, independent central review. Results Of 1298 pts included, 171 (13%) had baseline brain metastases. Median (range) follow-up was 10.9 (0.1–35.1) mo and 11.0 (0.1–34.9) mo in pts with and without brain metastases, respectively. HRs for OS and PFS were improved with pembro plus chemo vs chemo irrespective of baseline brain metastasis status (Table). ORR was higher and duration of response (DOR) was longer with pembro plus chemo vs chemo alone. All-cause grade 3–5 AEs with pembro plus chemo vs chemo alone occurred in 81.4% vs 70.3% of pts with brain metastases and 68.3% vs 65.6% without brain metastases.Table1483PDTableNOS HR (95% CI)PFS HR (95% CI)ORR, %Median DOR, mo (range)Brain metastasesPembro plus chemo1050.48 (0.32–0.70)0.44 (0.31–0.62)39.011.3 (1.1+ to 27.9+)Chemo6619.76.8 (1.3+ to 9.4)No brain metastasesPembro plus chemo6430.63 (0.53–0.75)0.55 (0.48–0.63)54.612.2 (1.1+ to 29.3+)Chemo48431.86.0 (1.4+ to 30.1+)+, response ongoing at data cutoff. Conclusions Pembro plus chemo provided clinical benefit for pts with NSCLC pts, regardless of presence/absence of stable brain metastases. The toxicity profile was manageable. Pembro plus chemo is standard of care therapy for pts with advanced NSCLC, including those with baseline brain metastases. Clinical trial identification NCT02039674; NCT02578680; NCT02775435. Editorial acknowledgement Rozena Varghese, PharmD, of C4 MedSolutions, LLC (Yardley, PA, USA), a CHC Group company, funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure S.F. Powell: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Vyriad; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Novartis. D. Rodriguez Abreu: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: Roche. C.J. Langer: Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): OSI (Astellas); Research grant / Funding (institution): Merck; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Advantage; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Inovio; Research grant / Funding (institution): Ariad; Research grant / Funding (institution): StemCentrx; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Guardant Health; Advisory / Consultancy: Merck; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Bayer/Onyx; Advisory / Consultancy: Abbott; Advisory / Consultancy: Morphotek; Advisory / Consultancy: Biodesix; Advisory / Consultancy: Clarient; Advisory / Consultancy: Caris Diagnostics; Advisory / Consultancy: Vertex; Advisory / Consultancy: Synta Pharmaceuticals; Advisory / Consultancy: Celgene; Advisory / Consultancy: Boehringer-Ingelheim; Advisory / Consultancy: Hospira; Advisory / Consultancy: Helsinn; Advisory / Consultancy: Synta Pharmaceuticals; Advisory / Consultancy: Clovis; Advisory / Consultancy: Ariad (Takeda); Advisory / Consultancy: Takai; Advisory / Consultancy: Regeneron;Officer / Board of Directors (data and safety monitoring committee member): Eli Lilly; Officer / Board of Directors (data and safety monitoring committee member): Amgen; Officer / Board of Directors (data and safety monitoring committee member): Synta Pharmaceuticals; Officer / Board of Directors (data and safety monitoring committee member): Agennix; Officer / Board of Directors (data and safety monitoring committee member): SWOG; Officer / Board of Directors (data and safety monitoring committee member): Peregrine Pharmaceuticals; Officer / Board of Directors (data and safety monitoring committee member): Incyte; Speaker Bureau / Expert testimony (CME presenter): PIK; Speaker Bureau / Expert testimony (CME presenter): PER; Speaker Bureau / Expert testimony (CME presenter): NOCR; Speaker Bureau / Expert testimony (CME presenter): Imedex; Speaker Bureau / Expert testimony (CME presenter): CCO; Speaker Bureau / Expert testimony (CME presenter): RTP; Speaker Bureau / Expert testimony (CME presenter): MLG; Speaker Bureau / Expert testimony (CME presenter): TRM; Speaker Bureau / Expert testimony (CME presenter): Web-MD. L. Paz-Ares: Honoraria (self), Spouse / Financial dependant: Roche; Honoraria (self), Spouse / Financial dependant: Lilly; Honoraria (self), Spouse / Financial dependant: Boehringer Ingelheim; Honoraria (self), Spouse / Financial dependant: AstraZeneca; Honoraria (self), Spouse / Financial dependant: Novartis; Honoraria (self), Spouse / Financial dependant: Pfizer; Honoraria (self), Spouse / Financial dependant: Amgen; Honoraria (self), Spouse / Financial dependant: BMS; Honoraria (self), Spouse / Financial dependant: MSD; Honoraria (self), Spouse / Financial dependant: Merck; Honoraria (self), Spouse / Financial dependant: Sanofi; Honoraria (self), Spouse / Financial dependant: PharmaMar; Honoraria (self), Spouse / Financial dependant: Servier; Honoraria (self), Spouse / Financial dependant: Sysmex; Honoraria (self), Spouse / Financial dependant: Incyte; Honoraria (self), Spouse / Financial dependant: Ipsen; Honoraria (self), Spouse / Financial dependant: Adacap; Honoraria (self), Spouse / Financial dependant: Bayer; Honoraria (self), Spouse / Financial dependant: Blueprint Medicines; Honoraria (self), Spouse / Financial dependant: Celgene; Officer / Board of Directors: Genomica; Research grant / Funding (institution): MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Pfizer. H. Kopp: Honoraria (self), Travel / Accommodation / Expenses: MSD; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Travel / Accommodation / Expenses: Sanofi; Honoraria (self): Roche; Honoraria (self), Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Amgen. J. Rodriguez-Cid: Research grant / Funding (institution): MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Celgene. D. Kowalski: Research grant / Funding (institution): MSD. Y. Cheng: Research grant / Funding (institution): MSD. T. Kurata: Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): Eli Lilly; Honoraria (self): Chugai; Honoraria (self): Ono; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim. M.M. Awad: Advisory / Consultancy: Merck. J. Lin: Full / Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. B. Zhao: Full / Part-time employment: Merck Sharp & Dohme Corp. M.C. Pietanza: Full / Part-time employment: Merck Sharp & Dohme Corp. B. Piperdi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme Corp. M.C. Garassino: Honoraria (self), Research grant / Funding (institution): Merck; Honoraria (self), Research grant / Funding (institution): BMS; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): Celgene; Honoraria (self), Research grant / Funding (institution): MedImmune; Honoraria (self): Incyte; Honoraria (self): Ignyta. All other authors have declared no conflicts of interest.