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

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

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.