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Proffered Paper 1 - NSCLC, metastatic

4311 - Pembrolizumab (pembro) plus platinum-based chemotherapy (chemo) for metastatic NSCLC: tissue TMB (tTMB) and outcomes in KEYNOTE-021, 189, and 407

Date

27 Sep 2019

Session

Proffered Paper 1 - NSCLC, metastatic

Presenters

Luis Paz-Ares

Citation

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

Authors

L. Paz-Ares1, C.J. Langer2, S. Novello3, B. Halmos4, Y. Cheng5, S.M. Gadgeel6, R. Hui7, S. Sugawara8, H. Borghaei9, R. Cristescu10, D. Aurora-Garg11, A. Albright10, A. Loboda11, J. Kobie10, J. Lunceford11, M. Ayers11, G.M. Lubiniecki11, M.C. Pietanza11, B. Piperdi10, M.C. Garassino12

Author affiliations

  • 1 Medical Oncology Dept., Hospital Universitario 12 de Octubre, Spanish National Cancer Research Center, Universidad Complutense and Ciberonc, 28041 - Madrid/ES
  • 2 Medicine, Abramson Cancer Center of the University of Pennsylvania, 08550 - Philadelphia/US
  • 3 Oncology, University of Turin, 10043 - Orbassano/IT
  • 4 Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, 10461 - Bronx/US
  • 5 Thoracic Oncology, Jilin Cancer Hospital, 130012 - Changchun/CN
  • 6 Oncology, Karmanos Cancer Institute (currently at University of Michigan, Ann Arbor, MI, USA), Detroit/US
  • 7 Medical Oncology, Westmead Hospital and the University of Sydney, Sydney/AU
  • 8 Pulmonary Medicine, Sendai Kousei Hospital, 980-0873 - Miyagi/JP
  • 9 Hematology And Oncology, Fox Chase Cancer Center, Philadelphia/US
  • 10 Oncology, Merck & Co., Inc., Kenilworth/US
  • 11 Oncology, Merck & Co., Inc., 07033 - Kenilworth/US
  • 12 Thoracic Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 - Milan/IT
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Abstract 4311

Background

Pembro + chemo improves efficacy as 1L therapy for metastatic squamous and nonsquamous NSCLC, regardless of PD-L1 TPS. We explored the relationship between tTMB and efficacy in KEYNOTE-021 C and G (nonsquamous; NCT02039674), 189 (nonsquamous; NCT02578680), and 407 (squamous; NCT02775435).

Methods

tTMB was determined by whole-exome sequencing of tumor and matched normal DNA. For each study, the association of tTMB (continuous log10 transformed) with outcomes for pembro + chemo and for chemo was assessed in pts with evaluable tTMB using Cox proportional hazards models (OS, PFS) and logistic regression (ORR); statistical significance was determined at the 0.05 level (no multiplicity adjustment). Clinical utility of tTMB on outcomes was assessed using a prespecified cutpoint of 175 mut/exome. Primary study endpoints were OS and PFS in KEYNOTE-189 and 407 and ORR in 021.

Results

tTMB was evaluable in 48% of treated pts in KEYNOTE-021 C and G, 48% in 189, and 56% in 407. Baseline characteristics and efficacy were similar in the tTMB-evaluable and total populations. tTMB (continuous log10) was not significantly associated with efficacy of pembro + chemo or chemo (minimum P values across studies: 1-sided .072 for ORR, .052 for PFS, and .081 for OS for pembro + chemo; 2-sided .086, .055, and .475, respectively, for chemo). Pembro + chemo improved OS and PFS for tTMB ≥175 and <175 mut/exome in KEYNOTE-189 and 407 (Table). In pembro + chemo–treated pts in KEYNOTE-021 G, ORR (95% CI) was 60.8% (38.5-80.3) in the 23 pts with tTMB <175 and 71.4% (47.8-88.7) in the 21 pts with tTMB ≥175 mut/exome.

Conclusions

In this exploratory analysis, tTMB was not significantly associated with efficacy of pembro + platinum-based chemo or of chemo alone as 1L therapy for metastatic NSCLC, regardless of histology. Pembro + chemo showed survival benefit in the tTMB-high and low subgroups for both squamous and nonsquamous NSCLC.Table:

LBA80

tTMB ≥175 mut/exomeatTMB <175 mut/exomea
KEYNOTE-189KEYNOTE-407KEYNOTE-189KEYNOTE-407
N, pembro + chemo1007310770
N, chemo34895280
OS, HR (95% CI)0.640.740.640.86
(0.38-1.07)(0.50-1.08)(0.42-0.97)(0.57-1.28)
PFS, HR (95% CI)0.320.570.510.68
(0.21-0.51)(0.41-0.81)(0.35-0.74)(0.48-0.96)
a

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

Clinical trial identification

KEYNOTE-021: NCT02039674, originally posted January 17, 2014; KEYNOTE-189: NCT02578680, originally posted October 19, 2015; KEYNOTE-407: NCT02775435, originally posted May 17, 2016.

Editorial acknowledgement

Melanie Leiby 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

L. Paz-Ares: Officer / Board of Directors: Genomica; Honoraria (self): Roche ; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Amgen; Honoraria (self): Sanofi; Honoraria (self): Pharamar; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self): Merck; Honoraria (self): Takeda; Honoraria (self): Celgene; Honoraria (self): Servier; Honoraria (self): Sysmex; Honoraria (self): Incyte; Honoraria (self): Ipsen; Honoraria (self): Adacap; Honoraria (self): Bayer; Honoraria (self): Blueprint; Leadership role: Altum Sequencing. C.J. Langer: Advisory / Consultancy, Research grant / Funding (institution): Merck & Co., Inc.; Advisory / Consultancy: AbbVie; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Celgene; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Takeda; Advisory / Consultancy: Bristol-Myers Squibb. S. Novello: Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Boehringer Ingelheim; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Eli Lilly. B. Halmos: Advisory / Consultancy, Research grant / Funding (institution): Merck & Co., Inc.; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Guardant Health; Advisory / Consultancy: Spectrum; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Genentech; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Mirati; Research grant / Funding (institution): Takeda. Y. Cheng: Research grant / Funding (institution): MSD. S.M. Gadgeel: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Xcovery; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Novocure; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Takeda; Research grant / Funding (institution): MSD. R. Hui: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Eli Lilly. S. Sugawara: Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Ono Pharmaceutical; Honoraria (self): AstraZeneca; Honoraria (self): Chugai Pharma; Honoraria (self): Nippon Boehringer Ingelheim; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Kyowa Hakko Kirin. H. Borghaei: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech; Advisory / Consultancy, Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck ; Advisory / Consultancy, Travel / Accommodation / Expenses: EMD-Serono; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Genmab; Advisory / Consultancy: Regeneron; Advisory / Consultancy: BioNTech; Advisory / Consultancy: Cantargia AB; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Axiom; Advisory / Consultancy: PharmaMar; Advisory / Consultancy: Takeda; Advisory / Consultancy: Huya Bio; Research grant / Funding (institution): Milennium; Research grant / Funding (institution): Merck/Celgene; Research grant / Funding (institution): BMS/Lilly; Full / Part-time employment: Fox Chase Cancer Center; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly. 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: Full / Part-time employment: Merck & Co., Inc.. A. Loboda: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. J. Kobie: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. J. Lunceford: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. M. Ayers: 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.. M.C. Garassino: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Lilly; Advisory / Consultancy: Roche; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Novartis; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): MedImmune.

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