Abstract 744P
Background
In the phase 2 KEYNOTE-052 trial in advanced UC, 18-gene T-cell–inflamed gene expression profile (GEP) was positively associated with response to pembro and stromal sig (stroma/EMT/TGF-β) was negatively associated. We explored association of these sigs with efficacy in the phase 3 KEYNOTE-045 trial of pembro vs chemo in platinum-refractory metastatic UC (mUC).
Methods
Univariate analyses using logistic regression (ORR) and Cox proportional hazard (PFS, OS), adjusted for ECOG PS, were performed, and nominal P values (1-sided, pembro; 2-sided, chemo) without multiplicity adjustment were calculated. Significance was prespecified at 0.05. Clinical utility of GEP and stromal sig was assessed using first tertile and median cutoffs.
Results
291/542 pts (53.7%) had RNA-seq data. GEP was associated with ORR (P=0.05) with pembro; a positive trend was observed for PFS (P=0.09) and OS (P=0.12). GEP was not associated with ORR (P=0.87), PFS (P=0.58), or OS (P=0.98) with chemo. HR estimates using prespecified GEP cutoff suggest trends toward improved PFS and OS for pembro vs chemo in GEP-high group (Table). Stromal sig was not associated with outcomes with pembro (P=0.15 [ORR], 0.30 [PFS], 0.40 [OS]) or chemo (P=0.42 [ORR], 0.09 [PFS], 0.12 [OS]). HR estimates using prespecified stromal sig cutoff suggest trends toward longer PFS and OS in ≥median group; this may be driven by poor performance of chemo in this group vs the hypothesized association with pembro (Table).
Conclusions
In this exploratory analysis in pts with mUC from KEYNOTE-045, GEP was positively associated with ORR to pembro but not chemo. GEP continues to serve as a good exploratory gene sig to support the MOA of pembro in highly inflamed tumors. Stromal sig was not associated with outcomes to pembro in KEYNOTE-045. Additional analyses are exploring differences in association of stromal sig with pembro between KEYNOTE-052 and KEYNOTE-045. Table: 744P
Clinical outcomes by GEP and stromal signature cutoff in KEYNOTE-045
| GEP≥first tertile | GEP≥first tertile | GEP| GEP | Stromal signature ≥median | Stromal signature ≥median | Stromal signature | Stromal signature | | |
| Pembro n=101 | Chemo n=93 | Pembro n=48 | Chemo n=49 | Pembro n=73 | Chemo n=73 | Pembro n=76 | Chemo n=69 | |
| ORR, % | 26.7 | 12.9 | 14.6 | 14.3 | 21.9 | 11.0 | 23.7 | 15.9 |
| PFS, HR (95% CI) | 0.81 (0.59-1.12) | -- | 1.53 (0.99-2.39) | -- | 0.86 (0.58-1.26) | -- | 1.13 (0.79-1.62) | -- |
| OS, HR (95% CI) | 0.64 (0.46-0.89) | -- | 1.01 (0.65-1.59) | -- | 0.58 (0.39-0.85) | -- | 0.92 (0.63-1.34) | -- |
Clinical trial identification
NCT02256436.
Editorial acknowledgement
Medical writing and/or editorial assistance was provided by Holly C. Cappelli, PhD, CMPP, and Dana Francis, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was 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
P. Grivas: Honoraria (self): AstraZeneca, Bayer, Biocept, Bristol-Myers Squibb, Clovis Oncology, Driver, EMD Serono, Exelixis, Foundation Medicine, Genentech, Genzyme, GlaxoSmithKline, Heron Therapeutics, Janssen, Merck, Mirati Therapeutics, Pfizer, Roche, Seattle Genetics, QED Ther; Honoraria (institution): KureIT; Advisory/Consultancy: AstraZeneca, Bayer, Biocept, Bristol-Myers Squibb, Clovis Oncology, Driver, EMD Serono, Exelixis, Foundation Medicine, Genentech, Genzyme, GlaxoSmithKline, Heron Therapeutics, Janssen, Merck, Mirati Therapeutics, Pfizer, Roche, Seattle Genetics, QED Ther; Speaker Bureau/Expert testimony, Educational unbranded activity (2017): Bristol-Myers Squibb; Travel/Accommodation/Expenses: AstraZeneca, Bayer, Biocept, Bristol-Myers Squibb, Clovis Oncology, Driver, EMD Serono, Exelixis, Foundation Medicine, Genentech, Genzyme, GlaxoSmithKline, Heron Therapeutics, Janssen, Merck, Mirati Therapeutics, Pfizer, Roche, Seattle Genetics, QED Ther; Research grant/Funding (institution): AstraZeneca, Bavarian Nordic, Bayer, Bristol-Myers Squibb, Clovis Oncology, Debiopharm, Genentech, Immunomedics, Merck, Mirati Therapeutics, Oncogenex, Pfizer. A.V. Balar: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Genentech; Advisory/Consultancy: Incyte; Advisory/Consultancy: Janssen; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Merck; Advisory/Consultancy: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): AstraZeneca/Medimmune; Advisory/Consultancy, Research grant/Funding (self): Nektar; Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Immunomedics. J. Vuky: Advisory/Consultancy: Seattle Genetics/Astellas; Research grant/Funding (institution): Celldex, Innocrin Pharma, Roche/Genentech, Novartis, Merck, Fortis Therapeutics. R. de Wit: Honoraria (self): Sanofi, Merck; Advisory/Consultancy: Janssen, Astellas, Clovis, Roche, Bayer; Research grant/Funding (institution): Sanofi, Bayer. N.J. Vogelzang: Research grant/Funding (institution), Clovis [Prostate cancer]; Aravive [Advanced renal cancer]; r; Genentech; MacroGenics; Merck; Nektar; Tolero [Advanced solid tumors]; Arvinas; AstraZeneca; eFFECTOR; Endocyte; Epizyme; ESSA; Kangpu; Kintor Suzhou; Modra [Metastatic castration-resistant prostate cancer]; Bristol-Myers Squibb; Calithera; Corvus; Eisai; Novartis [Renal cancer]; Exelixis [Renal and prostate cancers]; Immunomedics; Mirati; Seattle Genetics [Bladder cancer]; Myovant [Hormone-sensitive prostate cancer].: Amgen; Dendreon; Clovis; Aravive; Ar; Genentech; MacroGenics; Merck; Nektar; Tolero; Arvinas; AstraZeneca; eFFECTOR; Endocyte; Epizyme; ESSA; Kangpu; Kintor Suzhou; Modra; Bristol-Myers Squibb; Calithera; Corvus; Eisai; Novartis; Exelixis; Immunome; Advisory/Consultancy, Astellas; Clovis; Janssen; Sanofi-Genzyme [Prostate cancer]; Arvinas; AstraZeneca; ESSA; Kintor Suzhou; Modra [Metastatic castration-resistant prostate cancer]; Cancer Expert Now; Caris; Corvus; Genecentric; Genentech; Tolero [Advanced solid tumors]; Eisai [Advanced solid tumors, renal cancer]; Exelixis [Advanced solid tumors, renal and prostate cancers]; Pfizer; SWOG [Genitourinary cancer]; Novartis; OnQuality Pharma [Renal cancer]; Merck [Advanced solid tumors, genitourinary cancer].: Astellas; Clovis; Janssen; Sanofi-Genzyme; Arvinas; AstraZeneca; ESSA; Kintor Suzhou; Modra; Cancer Expert Now; Caris; Corvus; Genecentric; Genentech; Tolero; Eisai; Exelixis; Pfizer; SWOG; Novartis; OnQuality Pharma; Merck; Speaker Bureau/Expert testimony, AstraZeneca [Metastatic castration-resistant prostate cancer]; Bayer; Clovis; Sanofi Genzyme [Prostate cancer]; Caris [Advanced solid tumors]; Seattle Genetics [Bladder cancer]: AstraZeneca; Bayer; Clovis; Sanofi Genzyme; Caris; Seattle Genetics. T.K. Choueiri: Research grant/Funding (self), Research grant/Funding (institution): AstraZeneca, Alexion, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton,; Honoraria (self): AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfize; Advisory/Consultancy: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prom; Leadership role: Other present or past leadership roles: Director of GU Oncology Division at Dana-Farber and past President of medical Staff at Dana-Farber), member of NCCN Kidney panel and the GU Steering Committee, past chairman of the Kidney Cancer Association Medical ; Licensing/Royalties: Related to biomarkers of immune checkpoint blockers. D. Bajorin: Honoraria (self): Merck/MSD, Dragonfly, Genentech/Roche, AstraZeneca, Pfizer, Eli-Lilly, Farma Fidici, EMD-Serono; Honoraria (institution): Merck/MSD, Dragonfly; Advisory/Consultancy: Merck/MSD, Dragonfly, Eli-Lilly, Genentech/Roche, EMD-Serono, Farma Fidici, AstraZeneca; Travel/Accommodation/Expenses: Merck, Dragonfly, Eli-Lilly; Research grant/Funding (institution): Merck, Novartis, AstraZeneca, Pfizer. D. Castellano Gauna: Advisory/Consultancy: Janssen Oncology, Roche/Genentech, Astellas Pharma, AstraZeneca, Pfizer, Novartis, Ispen, Bristol-Myers Squibb, MSD Oncology, Bayer, Eli Lilly, Sanofi, Pierre Fabre, Boehringer Ingelheim; Travel/Accommodation/Expenses: Pfizer, Roche, Bristol-Myers Squibb, AstraZeneca Spain; Research grant/Funding (institution): Janssen Oncology. W. Gerritsen: Advisory/Consultancy: BMS, IqVia, Bayer, MSD, Sanofi, Janssen-Cilag; Speaker Bureau/Expert testimony: MSD; Research grant/Funding (self): Astellas, Bayer, Janssen-Cilag, Sanofi. H. Gurney: Honoraria (self): BMS, Roche, Astellas, Ipsen, Jansen, MSD, Pfizer, Merck; Advisory/Consultancy: BMS, Roche, Astellas, Ipsen, Jansen, MSD, Pfizer, Merck. D.I. Quinn: Honoraria (self): Astellas, AstraZeneca, BMS, Bayer, Janssen, Merck, Pfizer, Genentech, Roche, Seattle Genetics; Advisory/Consultancy: Astellas, AstraZeneca, BMS, Bayer, Janssen, Merck, Pfizer, Genentech, Roche, Seattle Genetics; Travel/Accommodation/Expenses: Astellas, AstraZeneca, BMS, Bayer, Merck, Pfizer, Genentech, Roche; Research grant/Funding (institution): Merck, Genentech, Pfizer, Bayer. S. Culine: Advisory/Consultancy: Bayer, Astellas, Takeda; Travel/Accommodation/Expenses: Ipsen, Janssen. Y. Fradet: Honoraria (self): Astellas, Sanofi, Janssen, TerSera; Advisory/Consultancy: Astellas, Sanofi, Janssen, TerSera; Research grant/Funding (institution): Merck, TerSera, IMVinc; Travel/Accommodation/Expenses: TerSera, Sanofi. A. Saadatpour: 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. A. Loboda: Full/Part-time employment: Merck & Co., Inc. J. Ma: 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. M. Rajasagi: 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. J.L. Godwin: 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. B.H. Moreno: 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; Honoraria (institution): Merck & Co., Inc., Kenilworth, NJ, USA. J. Bellmunt: Advisory/Consultancy: Pfizer, MSD, Merck, AstraZeneca, BMS, Roche-Genentech, Pierre Fabre; Travel/Accommodation/Expenses: Pfizer; Licensing/Royalties: UpToDate.