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Proffered Paper 1 - NSCLC, metastatic

3570 - Association between tissue TMB (tTMB) and clinical outcomes with pembrolizumab monotherapy (pembro) in PD-L1-positive advanced NSCLC in the KEYNOTE-010 and -042 trials

Date

27 Sep 2019

Session

Proffered Paper 1 - NSCLC, metastatic

Presenters

Roy S. Herbst

Citation

Annals of Oncology (2019) 30 (suppl_5): v851-v934. 10.1093/annonc/mdz394

Authors

R.S. Herbst1, G. Lopes2, D.M. Kowalski3, M. Nishio4, Y. Wu5, G. de Castro Junior6, P. Baas7, D. Kim8, M.A. Gubens9, R. Cristescu10, D. Aurora-Garg11, A. Albright10, M. Ayers11, A. Loboda11, J. Lunceford11, J. Kobie11, G.M. Lubiniecki11, M.C. Pietanza11, B. Piperdi11, T.S.K. Mok12

Author affiliations

  • 1 Medical Oncology, Yale University School of Medicine, Yale Cancer Center, 06520 - New Haven/US
  • 2 Oncology, Sylvester Comprehensive Cancer at the University of Miami, Miami/US
  • 3 Lung Cancer And Chest Tumours, Maria Sklodowska-Curie Memorial Cancer Centre-Institute of Oncology, 02-781 - Warsaw/PL
  • 4 Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 135-8550 - Tokyo/JP
  • 5 Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou/CN
  • 6 Clinical Oncology, Instituto do Câncer do Estado de São Paulo, São Paulo/BR
  • 7 Thoracic Oncology, The Netherlands Cancer Institute, 1066 CX - Amsterdam/NL
  • 8 Internal Medicine, Seoul National University Hospital, 110-744 - Seoul/KR
  • 9 Medicine, University of California, San Francisco, 94115 - San Francisco/US
  • 10 Oncology, Merck & Co., Inc., Kenilworth/US
  • 11 Oncology, Merck & Co., Inc., 07033 - Kenilworth/US
  • 12 State Key Laboratory Of Translational Oncology, The Chinese University of Hong Kong, Shatin - Hong Kong/HK
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Abstract 3570

Background

In randomized open-label trials, pembro monotherapy demonstrated an OS benefit vs chemo in pts with previously treated (KEYNOTE-010, NCT01905657) or treatment naïve (KEYNOTE-042, NCT02220894), PD-L1 + (TPS ≥1%), advanced NSCLC. Associations between tTMB and efficacy were retrospectively explored in a subset of pts with evaluable tTMB in these trials.

Methods

tTMB was determined by whole exome sequencing of tumor and matched normal DNA. tTMB was evaluable for 253 (24%) pts in KEYNOTE-010 and 793 (62%) pts in KEYNOTE-042. For each study, association of tTMB (continuous log10 scale) with outcomes in each arm was evaluated using Cox proportional hazards models (OS, PFS) and logistic regression (ORR). Statistical significance was determined at the 0.05 level, unadjusted for multiplicity. Clinical utility of tTMB was assessed using a prespecified cutpoint of 175 mut/exome*.

Results

Baseline characteristics of the tTMB evaluable subset and total study population were similar. tTMB was not correlated with TPS (continuous score) in both pembro and chemotherapy (chemo) arms (r < 0.18). tTMB was associated with OS, PFS and ORR for pembro (pembro arms pooled) in KEYNOTE-010 (1-sided p = 0.006, 0.001, 0.009, respectively) and in KEYNOTE-042 (all 1-sided p < 0.001); whereas tTMB was in general not associated with outcomes for chemo. In both trials, improvements in OS, PFS and ORR were generally observed for pembro treated pts with high tTMB ≥175 (Table).Table:

LBA79

TMB ≥175 Mut/exome*TMB <175 Mut/exome*
KEYNOTE-010Pembroa N = 81Chemob N = 51Pembroa N = 83Chemob N = 38
Median OS (95% CI)14.1 (10.0-19.2)7.6 (5.0-10.7)9.3 (8.3-12.5)7.2 (4.5-14.3)
OS HR (95% CI)0.56 (0.38-0.83)0.85 (0.56-1.30)
Median PFS (95% CI)4.2 (2.2-10.0)2.4 (2.1-6.0)3.7 (2.1-4.5)3.4 (2.1-7.5)
PFS HR (95% CI)0.59 (0.40-0.87)1.09 (0.72-1.63)
ORR % (95% CI)23.5 (14.8-34.2)9.8 (3.3-21.4)16.9 (9.5-26.7)21.1 (9.6-37.3)
KEYNOTE-042Pembroc N = 189Chemod N = 165Pembroc N = 234Chemod N = 214
Median OS (95% CI)21.9 (17.0-26.7)11.6 (9.9-14.2)12.0 (9.2-14.8)12.3 (11.3-16.2)
OS HR (95% CI)0.62 (0.48-0.80)1.09 (0.88-1.36)
Median PFS (95% CI)6.3 (5.5-8.5)6.5 (6.2-8.1)4.1 (3.1-4.3)6.3 (6.1-8.1)
PFS HR (95% CI)0.75 (0.59-0.95)1.27 (1.04-1.55)
ORR % (95% CI)34.4 (27.5-41.9)30.9 (24.0-38.6)18.8 (14.0-24.4)22.4 (17.0-28.6)
*

Cutpoint derived by meta-analysis of TMB and gene expression data from pembro clinical trials across multiple tumor types;

a

pembro 10 mg/kg (Q3W)+pembro 2 mg/kg Q3W;

b

docetaxel 75 mg/m2 Q3W;

c

pembro 200 mg Q3W;

d

platinum-based chemo.

Conclusions

In this exploratory analysis, associations between higher tTMB levels and improved clinical outcome with pembro monotherapy were observed in pts with PD-L1+ NSCLC. While the results suggest that tTMB may provide additional information regarding the clinical benefit of pembro monotherapy among pts with PD-L1+ NSCLC tumors, the analyses and effect estimates were limited to observational subsets of the randomized cohorts.

Clinical trial identification

KEYNOTE-10 (NCT01905657), originally posted July 23, 2013; KEYNOTE-042 (NCT02220894), originally posted August 20, 2014.

Editorial acknowledgement

Joanne Tomassini of 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

R.S. Herbst: Advisory / Consultancy: AbbVie Pharmaceuticals; Advisory / Consultancy: ARMO Biosciences; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Biodesix; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly and Company; Advisory / Consultancy: EMD Serrano; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Genmab; Advisory / Consultancy: Heat Biologics; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Loxo Oncology; Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme Corp.; Advisory / Consultancy: Nektar; Advisory / Consultancy: NextCure; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Shire PLC; Officer / Board of Directors: Junshi Pharmaceuticals; Advisory / Consultancy: Spectrum Pharmaceuticals; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Tocagen; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Neon Therapeutics; Advisory / Consultancy: Infinity Pharmaceuticals. G. Lopes: Research grant / Funding (institution): MSD; Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GI Therapeutics; Honoraria (self), Research grant / Funding (self): Bristol-Myers Squibb; Honoraria (self), Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: ER Squibb Sons, LLC; Travel / Accommodation / Expenses: Janssen; Honoraria (self), Research grant / Funding (self): Merck. D.M. Kowalski: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: Pfizer; Advisory / Consultancy: MSD; Advisory / Consultancy: Bristol-Myers Squibb. M. Nishio: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Daiichi Sankyo Healthcare; Advisory / Consultancy: Merck Serono; Research grant / Funding (institution): Astellas. Y. Wu: Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self): Sanofi; Advisory / Consultancy: Merck & Co., Inc.. G. de Castro Junior: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy: TEVA; Advisory / Consultancy: Yuhan; Advisory / Consultancy: Merck Serono. P. Baas: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (institution), Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Aldeyra Therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Theradex. D. Kim: Research grant / Funding (institution): Alpha Biopharma; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Hanmi; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): ONO Pharmaceuticals; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): TP Therapeutics; Research grant / Funding (institution): Xcovery; Research grant / Funding (institution): Yuhan. M.A. Gubens: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Beyond Spring; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Heron; Advisory / Consultancy: Takeda; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Merck & Co., Inc.; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): Roche. R. Cristescu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. D. Aurora-Garg: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. A. Albright: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. M. Ayers: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. A. Loboda: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. J. Lunceford: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. J. Kobie: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. G.M. Lubiniecki: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. M.C. Pietanza: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. B. Piperdi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. T.S.K. Mok: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): SFJ Pharmaceuticals; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Xcovery; Honoraria (self), Advisory / Consultancy: Roche/Genentech; Honoraria (self), Leadership role, Shareholder / Stockholder / Stock options: Hutchinson MediPharma; Honoraria (self): Janssen; Honoraria (self): Takeda; Honoraria (self): Fishawack Facilitate Ltd; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: ACEA Biosciences, Celgene, Vertex, geneDecode, OncoGenex, Ignyta, Cirina; Leadership role, Shareholder / Stockholder / Stock options: Sanomics Ltd; Shareholder / Stockholder / Stock options: Cirina; Full / Part-time employment: Chinese University of Hong Kong; Non-remunerated activity/ies, Board of director for ASCO; Track chair for ESMO, ASCO.

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