Albumin as a simple criterion to reduce early mortality (EM) in gastric cancer (GC) trials

Background: Some clinical trials in advanced/metastatic GC have observed that >20% of patients succumb to their disease within 3 months of enrollment. It is likely that these patients were poor performing at the time of enrollment and their inclusion is not suitable for the assessment of the efficacy of experimental therapies. This issue can be addressed by improving trial eligibility criteria. Methods: Data from KEYNOTE-061 (NCT02370498) were analyzed retrospectively to identify general baseline factors for predicting EM using >70 baseline measurements (eg, demographic and clinical variables, lifestyle factors, tumor-related measurements, lab tests, and other study-specific measurements). An exclusion criterion for patients at risk for EM was then proposed based on the identified baseline factor. KEYNOTE-062 (NCT02494583), an independent study of 740 patients, was used to validate the proposed exclusion criterion for EM. Both steps were done without knowledge of the study treatment. The impact of the proposed criterion on treatment was further evaluated after unblinding in both studies. Results: Using data from KEYNOTE-061, albumin level was the top-ranked baseline factor correlating to EM. An exclusion criterion of albumin ≤3 g/dL was proposed, which identified 9% of the trial population. The EM rate was 53% in patients with albumin ≤3 g/dL versus 20% in all patients regardless of albumin level (2.65 times enrichment). When applied to KEYNOTE-062, the same albumin criterion identified 8% of the trial population and the EM rate was 2.1 times enriched over that in all patients regardless of albumin level. After unblinding to study treatment and use of the proposed criterion, subsequent analysis showed improvement of pembrolizumab over the comparator in both trials. Conclusions: Our exploratory analysis identified blood albumin level as an important measurement correlated to EM in GC studies. Exclusion of patients with albumin ≤3 g/dL may reduce EM in clinical trials to enable a more appropriate assessment of clinical efficacy. This exploratory analysis suggests that the potential prognostic role(s) of serum albumin in select indications warrants further examination in immuno-oncology therapies in the clinical setting. Clinical trial identification: KEYNOTE-061, NCT02370498; KEYNOTE-062, NCT02494583. Editorial acknowledgement: Medical writing and/or editorial assistance provided by Holly C. Cappelli, PhD, CMPP, and Dana Francis, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA) and funded by Merck Sharp & Dohme Corp. Legal entity responsible for the study: Merck Sharp & Dohme Corp. Funding: Merck Sharp & Dohme Corp. Disclosure: M. Ozguroglu: Honoraria (self): Janssen, Astellas, Novartis; Honoraria (institution): JANSSEN; Advisory/Consultancy: MSD, SANOFI; Speaker Bureau/Expert testimony: AstraZeneca; Travel/Accommodation/Expenses: BMS, AstraZeneca. K. Shitara: Honoraria (self): Novartis, AbbVie, and Yakult; Advisory/Consultancy: Astellas, Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono, MSD, Taiho, Novartis, AbbVie, and GlaxoSmithKline; Research grant/Funding (institution): Astellas, Lilly, Ono, Sumoitomo Dainippon, Daiichi Sankyo, Taiho, Chugai, MSD, and Medi Science. K-W. Lee: Honoraria (self): Bristol-Myers Squibb, Eli Lilly, and Genexine; Research grant/Funding (self): Ono Pharmaceutical, Merck Sharp & Dohme Corp., AstraZeneca/MedImmune, Merck KGaA, Pfizer, MacroGenics, Green Cross Corporation, Five Prime Therapeutics, Pharmacyclics, LSK BioPharma, ALX Oncology, Zymeworks, BeiGene, Genexine, Daiichi Sankyo, and Taiho Ph. C.S. Fuchs: Leadership role: CytomX Therapeutics, Evolveimmune Therapeutics; Shareholder/Stockholder/Stock options: CytomX and Entrinsic Health exercised stock options; Advisory/Consultancy: Agios, Bain Capital, CytomX, Daiichi Sankyo, Eli Lilly, Entrinsic Health, Genetech, Merck, Taiho, Unum. H.C. Chung: Honoraria (self): Merck-Serono, Lilly, Foundation Medicine; Advisory/Consultancy: Taiho, Celltrion, MSD, Lilly, Quintiles, BMS, Merck-Serono, Gloria, Beigene, Amgen, Zymework; Research grant/Funding (self): Lilly, GSK, MSD, Merck-Serono, BMS/Ono, Taiho, Amgen, Beigene. M. Di Bartolomeo: Honoraria (self): Lilly spa; Servier; Advisory/Consultancy: Taiho, Celltrion, MSD, Lilly, Quintiles, BMS, Merck-Serono, Gloria, Beigene, Amgen, Zymework; Research grant/Funding (institution): Lilly, GSK, MSD, Merck-Serono, BMS/Ono, Taiho, Amgen, Beigene. J. Chao: Advisory/Consultancy: Amgen, Macrogenics, Ono Pharmaceuticals, Foundation Medicine; Speaker Bureau/Expert testimony: Merck; Travel/Accommodation/Expenses: Amgen, Foundation Medicine, Macrogenics; Research grant/Funding (self): Merck, Brooklyn Immunotherapeutics. Z.A. Wainberg: Advisory/Consultancy: Merck, Ibsen, Lilly, Five prime, QED, Molecular Templates, Daiichi, Astra Zeneca; Travel/Accommodation/Expenses: Lilly, Merck, Novartis, Daiichi. C. Caglevic: Honoraria (self): Andes Biotechnologies; Advisory/Consultancy: BMS, MSD, Roche, Boehrnger Ingelheim; Speaker Bureau/Expert testimony: MSD, BMS, Lilly, Roche; Research grant/Funding (self): MSD, Medivation, AstraZeneca, Roche, Astellas Pharma, BMS; Travel/Accommodation/Expenses: BMS, Roche, MSD. E. Van Custem: Advisory/Consultancy: Array, Astrazeneca, Bayer, Biocartis, Bristol-Myers Squibb, Celgene, Daiichi, Halozyme, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Pierre-Fabre, Roche, Servier, Sirtex, Taiho; Research grant/Funding (institution): Bayer, Boehringer Ingelheim, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier paid to the institution. M. Garrido: Honoraria (self): BMS, MSD, Novartis, Roche, Pfizer, Bayer; Advisory/Consultancy: MSD, Bayer; Speaker Bureau/Expert testimony: MSD, BMS; Travel/Accommodation/Expenses: BMS, Novartis. J. Lee: Advisory/Consultancy: Oncologie, Seattle Genetics; Research grant/Funding (self): Astra Zeneca, Merck Sharp and Dohme, Eli Lilly and Company. J. Ma, Z.A. Cao, C-S. Shih, P. Bhagia: Full/Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Shareholder/Stockholder/Stock options: Merck & Co., Inc., Kenilworth, NJ, USA. S. Shah: Full/Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. J. Tabernero: Advisory/Consultancy: Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Partn. All other authors have declared no conflicts of interest.