843P - Association of gene expression signatures and TMB with response to pembrolizumab (pembro) in patients (pts) with recurrent ovarian cancer (ROC) enrolled in KEYNOTE-100

Background

Pembro had modest activity in pts with advanced ROC (platinum-resistant and platinum-sensitive) whose disease progressed after platinum-based therapy and who received ≤5 lines of therapy (N=376) in the phase II KEYNOTE-100 study (NCT02674061). Pan-tumor TMB data were previously presented. In a prespecified analysis, we explored the association of RNA-seq–based gene expression signatures and whole exome sequencing (WES)-based TMB and outcomes to pembro in pts with ROC in KEYNOTE-100.

Methods

RNA-seq population included pembro-treated pts in the training set (cohort A subset) with RNA-seq and clinical data. We analyzed association of 9 non–T-cell–inflamed GEP consensus signatures with ORR, PFS, and OS. 1-sided P values were calculated using logistic regression (ORR) and Cox PH regression at α=0.10; data were adjusted for multiplicity. WES population included pembro-treated pts with WES TMB and clinical data. We analyzed association of TMB with outcomes with the prespecified cutoff of 175 mut/exome. Clinical data cutoff: Feb 2, 2018.

Results

RNA-seq population comprised 78/376 (20.7%) pts. No RNA-seq consensus signatures were significantly associated with ORR, PFS, or OS (P >0.10); angiogenesis signature showed a negative trend with area under the receiver operating characteristic curve (AUROC) of 0.64 (95% CI, 0.50-0.77) (Table). WES population comprised 293/376 (77.9%) pts; <5% had TMB ≥175 mut/exome. A >2-fold enrichment in ORR was observed in pts with TMB ≥175 mut/exome vs pts with TMB <175 mut/exome (16.7% vs 7.5%, respectively).

Conclusions

In this prespecified exploratory analysis from KEYNOTE-100 with limited sample sizes, no gene expression signatures were significantly associated with response to pembro monotherapy in pts with advanced ROC. Only a small fraction of tumors was TMB high by the prespecified cutoff of 175 mut/exome, but trends observed suggest enrichment for response at that cutoff.

Clinical trial identification

NCT02674061.

Editorial acknowledgement

Medical writing and 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.A. Ledermann: Advisory/Consultancy: AstraZeneca; Clovis Oncology; Pfizer; Tesaro/GSK; Seattle Genetics; Artios; MSD/Merck; Eisai, Amgen; Speaker Bureau/Expert testimony: AstraZeneca/MSD; Clovis Oncology; GSK; Officer/Board of Directors: Vice President, ESGO; Research grant/Funding (institution): MSD/Merck; AstraZeneca; Travel/Accommodation/Expenses: Clovis Oncology; Full/Part-time employment: University College London. R. Shapira-Frommer: Honoraria (self): MSD, BMS, Novartis, Medison, AstraZeneca, Neopharm; Advisory/Consultancy: VBL Therapeutics, Clovis Oncology, MSD. A.D. Santin: Advisory/Consultancy: Merck; Advisory/Consultancy: Tesaro; Research grant/Funding (institution): Puma, Immunomedics, Gilead, Synthon, Merck, Tesaro, Boehringer-Ingelheim, Genentech, R-PHARM-USA. S. Pignata: Honoraria (self): AstraZeneca, MSD, Pfizer, GSK, Clovis Oncology, PharmaMar, Incyte, Roche; Research grant/Funding (institution): Roche, MSD. AstraZeneca, Pfizer. I.B. Vergote: Advisory/Consultancy: Amgen GmbH, AstraZeneca NV, AstraZeneca UK Ltd, AstraZeneca Belux, Clovis Oncology Inc, Carrick Therapeutics, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genmab A/S-Genmab BV, Genmab US, GSK GlaxoSmithKline Pharmaceuticals NV, Immunogen Inc, Me; Advisory/Consultancy: Octimet Oncology NV, Oncoinvent AS, PharmaMar-Doctaforum Servicios SL, Roche NV, Sotio a.s., Tesaro Inc, Tesaro Bio GmbH, Deciphera Pharmaceuticals, Verastem Oncology; Research grant/Funding (institution), contracted research (via KULeuven): Oncoinvent AS, Genmab; Research grant/Funding (institution), grant = corporate sponsored research: Amgen, Roche; Travel/Accommodation/Expenses: Amgen, MSD/Merck Zurich and USA, Tesaro, AstraZeneca, Roche. F. Raspagliesi: Honoraria (self): Tesaro; Research grant/Funding (institution): Tesaro, Roche, MSD, AstraZeneca, PharmaMar, Clovis. G.S. Sonke: Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Roche. J. Sehouli: Honoraria (self): Roche, Roche Diagnostics, PharmaMar, AstraZeneca, Clovis, Tesaro/GSK; Honoraria (institution): Roche, Roche Diagnostics, PharmaMar, AstraZeneca, Clovis, Tesaro/GSK; Advisory/Consultancy: Roche, Roche Diagnostics, PharmaMar, AstraZeneca, Clovis, Tesaro, Amgen, GSK, Novocure, Pfizer, MSD; Research grant/Funding (self): Lilly, Roche, GSK, Clovis; Research grant/Funding (institution): Roche, Roche Diagnostics, PharmaMar, AstraZeneca, Clovis, Tesaro/GSK, Novocure, PharmaMar; Travel/Accommodation/Expenses: Lilly, Roche, GSK, Clovis. N. Colombo: Honoraria (self): Roche, PharmaMar, AstraZeneca, Clovis, GSK, Amgen, MSD, Immunogen, Biocad, Pfizer; Advisory/Consultancy: PharmaMar, AstraZeneca, Clovis, GSK, Amgen, MSD, Immunogen, Biocad, Pfizer; Travel/Accommodation/Expenses: PharmaMar. A. González Martín: Speaker Bureau/Expert testimony: Roche, AstraZeneca, Tesaro, PharmaMar; Advisory/Consultancy: Roche, AstraZeneca, Tesaro, PharmaMar; Advisory/Consultancy: Clovis, Pfizer/Merck, ImmunoGen, MSD, Genmab, Oncoinvent. A. Oaknin: Advisory/Consultancy: Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro, Inmunogen, Genmab; Travel/Accommodation/Expenses: Roche, AstraZeneca, and PharmaMar; Research grant/Funding (institution): AbbVie Deutschland, Ability Pharmaceuticals, Advaxis Inc., Aeterna Zentaris, Amgem, SA, Aprea Therapeutics AB, Clovis Oncology Inc, Eisai limited LTD, F. Hoffmann. La Roche Ltd., Regeneron Pharmaceuticals, Immunogen Inc., Merck, Sharp & Dohme de España SA; Officer/Board of Directors: Grupo Español de Investigación en Cáncer de Ovario (GEICO). A. Saadatpour, J. Kobie, P. Jelinic: Full/Part-time employment: Merck & Co., Inc.; Shareholder/Stockholder/Stock options: Merck & Co., Inc. K. Stein: Full/Part-time employment: Merck & Co., Inc. U.A. Matulonis: Advisory/Consultancy: Merck; Advisory/Consultancy: Novartis; Travel/Accommodation/Expenses: AstraZeneca. All other authors have declared no conflicts of interest. Table: 843P

Association between consensus signatures and clinical outcomes with pembrolizumab