Abstract 747P
Background
In the phase 2 KEYNOTE-052 trial (NCT02335424), 1L pembro monotherapy showed antitumor activity and acceptable safety in cisplatin-ineligible pts with UC (N = 374). In the phase 3 KEYNOTE-045 trial (NCT02256436), pembro significantly prolonged OS with a better safety profile vs chemotherapy (chemo; paclitaxel, docetaxel, or vinflunine) in platinum-refractory advanced UC (N = 542). Prior data showed an association between TMB and response to anti–PD-1 therapies in UC. We explored the association of TMB with efficacy with pembro.
Methods
In pts from KEYNOTE-052 and KEYNOTE-045 with TMB data assessed by whole-exome sequencing of tumor samples and matched normal DNA, the association of TMB (as a continuous variable) with ORR, PFS, and OS was evaluated. Testing using logistic regression (ORR) and Cox proportional hazard (PFS; OS), adjusted for ECOG PS, was performed; nominal P values were calculated without multiplicity adjustment (1-sided, pembro; 2-sided, chemo). Clinical utility of TMB was assessed using prespecified cutoff of 175 mut/exome in KEYNOTE-045.
Results
In KEYNOTE-052, 231 pts (62%) had TMB data; prevalence of TMB ≥175 mut/exome was 39%. Higher TMB was significantly associated with higher ORR (P < 0.001) and longer PFS (P = 0.001) and OS (P = 0.026) with pembro. The area under the ROC curve for TMB and response was 0.67 (95% CI, 0.59-0.75). In KEYNOTE-045, 370 pts (68%) had TMB data; prevalence of TMB ≥175 mut/exome was 31%. Higher TMB was significantly associated with higher ORR (P = 0.008) and longer PFS (P = 0.002) and OS (P = 0.014) with pembro but not chemo (P = 0.51, 0.56, and 0.23, respectively); outcomes based on TMB cutoff are reported in Table. Table: 747P
Outcomes based on TMB cutoff in KEYNOTE-045 trial
| TMB ≥175 mut/exome | TMB ≥175 mut/exome | TMB <175 mut/exome | TMB <175 mut/exome | |
| Pembro n = 55 | Chemo n = 61 | Pembro n = 133 | Chemo n = 121 | |
| ORR, % | 34.5 | 13.1 | 15.8 | 14.0 |
| PFS, HR (95% CI) | 0.65 (0.42-1.00) | - | 1.19 (0.91-1.55) | - |
| OS, HR (95% CI) | 0.66 (0.42-1.04) | - | 0.72 (0.55-0.96) | - |
Conclusions
In pts with advanced UC, TMB was associated with improved clinical outcomes with pembro monotherapy. In KEYNOTE-045, pembro improved OS vs chemo regardless of TMB.
Clinical trial identification
NCT02256436 and NCT02335424.
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
J. Bellmunt: Advisory/Consultancy: Pfizer, MSD, Merck, AstraZeneca, BMS, Roche-Genentech, Pierre Fabre; Travel/Accommodation/Expenses: Pfizer; Licensing/Royalties: UpToDate. R. de Wit: Honoraria (self): Sanofi, Merck; Advisory/Consultancy: Janssen, Astellas, Clovis, Roche, Bayer; Research grant/Funding (institution): Sanofi, Bayer. 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. M.A. Climent: Honoraria (self): Janssen, Astellas, BMS, MSD, Roche, Pfizer, Sanofi, Bayer, AstraZeneca; Advisory/Consultancy: MSD, BMS, Roche, EUSA, Astellas, Pfizer, Ipsen; Travel/Accommodation/Expenses: Astellas, BMS, Ipsen, Pfizer, Janssen. D.P. Petrylak: Advisory/Consultancy: Ada Cap (Advanced Accelerator Applications) Amgen, Astellas, AstraZeneca, Bayer, Bicycle Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Eli Lilly, Exelixis, Incyte, Janssen, Mirati, Monopteros, Pfizer, Pharmacyclics, Roche, Sea; Shareholder/Stockholder/Stock options, Sold 10/2019: Bellicum, Tyme; Research grant/Funding (institution), Denotes study trials that have terminated: Ada Cap (Advanced Accelerator Applications), Agensys Inc, Astellas, AstraZeneca, Bayer, BioXcel Therapeutics, Bristol Myers Squibb, Clovis Oncology, Eisai, Eli Lilly, Endocyte, Genentech, Innocrin, MedImmune, Medivation, Merck, Mirati, Novartis, Pfi. J-L. Lee: Honoraria (self): Bristol-Myers Squibb Korea, Amgen Korea, Astellas Korea, Pfizer Korea ; Advisory/Consultancy: Pfizer Korea, Sanofi Aventis Korea, Bristol Myers Squibb Korea, MSD Korea, Alteogene, GI Innovation; Research grant/Funding (institution): fizer, Janssen, Novartis, Bristol Myers Squibb, Roche/Genetech, AstraZeneca, MSD, Bayer Shering, Seattle Genetics. L. Fong: Research grant/Funding (self): AbbVie, Bavarian Nordic, BMS, Dendreon, Janssen, Merck, Roche/Genentech. A. Necchi: Honoraria (self): Roche, Merck, AstraZeneca, Janssen; Advisory/Consultancy: Merck, AstraZeneca, Janssen, Incyte, Roche, Rainier Therapeutics, Clovis Oncology, Bayer, and Astellas/Seattle Genetics, Ferring, Immunomedics; Research grant/Funding (institution): Merck, Ipsen, AstraZeneca. C.N. Sternberg: Advisory/Consultancy: Pfizer, MSD, Merck, AstraZeneca, Astellas, Sanofi-Genzyme, Roche-Genentech, Incyte, Medscape, UroToday; Advisory/Consultancy: Pfizer, MSD, Merck, AstraZeneca, Astellas, Sanofi-Genzyme, Roche-Genentech, Incyte, Medscape, UroToday. P. Grivas: Honoraria (self): eron Therapeutics, Janssen, Merck, Mirati Therapeutics, Pfizer, Roche, Seattle Genetics, QED Therapeutics; 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 Thera; Speaker Bureau/Expert testimony: 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 Thera; Research grant/Funding (institution): AstraZeneca, Bavarian Nordic, Bayer, Bristol-Myers Squibb, Clovis Oncology, Debiopharm, Genentech, Immunomedics, Merck, Mirati Therapeutics, Oncogenex, Pfizer. P.H. O’Donnell: Honoraria (self): ates, FirstWord Publication; Advisory/Consultancy: Merck; Research grant/Funding (institution): Boehringer Ingelheim, Merck, Genentech/Roche, AstraZeneca/MedImmune, Acerta Pharma, Janssen, Seattle Genetics, Bristol-Myers Squibb; Travel/Accommodation/Expenses: Merck, Seattle Genetics/Astellas, Genentech/Roche, Janssen. T. Powles: Honoraria (self): BMS, Seattle Genetics, Ipsen, Merck. MSD, Novartis, Pfizer ; Advisory/Consultancy: AstraZeneca, BMS, Exelexis, Incyte, Ipsen, Merck/MSD, Novartis, Pfizer, Seattle Genetics ; Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca, Roche. E.R. Plimack: Honoraria (institution): ASCO GU, Clinical Care Options, Fox Chase Cancer Center, Mt. Sinai Ichan School of Medicine, Medscape, NCCN, OncLive, PER, Research to Practice, Spire Learning, University of Pennsylvania, Thomas Jefferson Kimmel Cancer Center; Advisory/Consultancy: Flatiron, Genentech, Merck, Seattle Genetics; Research grant/Funding (institution), Data safety montioring: AstraZeneca, Pfizer, Infinity Pharma: Astellas, BMS, Genentech, Merck. R. Cristescu: 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. Lunceford: Full/Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. J. Ma: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck & Co., Inc.. M. Rajasagi: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck & Co., Inc.. J.L. Godwin: Full/Part-time employment: Merck & Co., Inc.. B.H. Moreno: Honoraria (institution), Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck & Co., Inc.. 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.