TILs have been observed in TNBC and are thought to represent pre-existing antitumor immunity. Thus, TILs could be a biomarker for response to immune checkpoint blockade. We assessed if TIL levels were associated with response to pembro monotherapy in the phase 2 KEYNOTE-086 study of previously treated mTNBC of any PD-L1 expression (cohort A) or previously untreated, PD-L1–positive mTNBC (cohort B) (NCT02447003).
Stromal TILs were quantified by a single pathologist blinded to clinical data using a published method of light microscopy of H&E-stained slides obtained from tumor biopsies. PD-L1 expression was assessed using the PD-L1 IHC 22C3 pharmDx. Response was assessed every 9 wk for 12 mo, then every 12 wk (RECIST v1.1, central review). Relationships between transformed TIL levels and ORR and DCR (CR + PR + SD ≥ 24 wk) were assessed using logistic regression adjusted for cohort (A vs B) and biopsy site (lymph node vs non-lymph node). All P values are 1 sided.
193 of the first 222 patients (pts) enrolled had evaluable tumor samples: 147 from cohort A, 46 from cohort B; 146 samples were newly collected (mostly from metastatic sites), 47 were archival (mostly from primary breast tumors). Median [IQR] TIL level was higher in cohort B vs A (17.5% [6.2-57.5%] vs 5% [1-10%], Wilcoxon rank sum P < .001), and in archival vs newly collected samples (10% [5-40%] vs 5% [1.2-15%], P < .001), and lymph node vs non-lymph node samples (10% [5-50%] vs 5% [2-15%], P = .01). ORR in pts with TIL level ≥ vs < median was 6% vs 2% in cohort A and 39% vs 9% in cohort B. Median (IQR) TIL level in responders vs nonresponders was 10% (7.5-25%) vs 5% (1-10%) in cohort A and 50% (5-70%) vs 15% (5-37.5%) in cohort B. In the combined cohorts, higher TIL levels were associated with significantly improved ORR (odds ratio 1.26, 95% CI 1.03- 1.55, P = .01) and DCR (odds ratio 1.22, 95% CI 1.02-1.46, P = .01). Area under the ROC curve was 0.75 for ORR and 0.69 for DCR. PD-L1 expression significantly correlated with TIL levels (ρ = 0.4962, P < .001).
TIL levels can identify pts with mTNBC with a greater chance of achieving response to pembro monotherapy, particularly in the first-line setting.
Clinical trial identification
ClinicalTrials.gov number NCT02447003, originally posted May 14, 2015, KEYNOTE-086; EudraCT number 2015-000294-13, originally entered April 4, 2015
Legal entity responsible for the study
Merck & Co., Inc.
Merck & Co., Inc.
S. Loi: Institution receives funding from Merck & Co., Inc. S. Adams: Study funding to the institution from Merck & Co., Inc. P. Schmid: Consulting or advisory role: AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Genentech/Roche, Merck & Co., Inc., Novartis, Pfizer, Puma Biotechnology; research funding (all to institution): Astellas Pharma, AstraZeneca, Genentech, Medivation, Novartis, Oncogenex. J. Cortés: Stock (self): MedSIR; honoraria (self): Roche, Novartis, Eisai, Celgene, Pfizer; consulting or advisory role (self): Roche, Celgene, AstraZeneca, Cellestia Biotech, Biothera Pharmaceutical. D.W. Cescon: Funds to institution for clinical trials: Merck & Co., Inc. E.P. Winer: Consulting fees: Genentech, Leap, Tesaro; research funding: Genentech, Merck & Co., Inc. D.L. Toppmeyer: Prof. Toppmeyer reports salary and stock options (husband): Novartis; consulting fees (self): Merck & Co., Inc., Novartis. H.S. Rugo: Funds to institution for contracted research: Merck & Co., Inc., Eli Lilly, Novartis, Pfizer, OBI, Macrogenics, Eisai, Roche. M. De Laurentiis: Advisory board member: Amgen, AstraZeneca, Cengene, Ipsen, Novartis, Pfizer, Roche; speakers\' bureau: Novartis, Pfizer, Roche; research funding: Roche; Honoraria: Amgen, AstraZeneca, Cengene, Ipsen, Novartis, Pfizer, Roche. R. Nanda: Advisory board member: AstraZeneca, Genentech, Merck & Co., Inc., Peregrine, Pfizer, Puma, Syndax; Research funding: Celgene, Corcept Therapeutics, Merck & Co., Inc.; Other (DSMB member): G1 Therapeutics. A. Tan: Research funding to the insitution from Merck & Co., Inc. A. Wang: Salary: Merck & Co., Inc. G. Aktan, V. Karantza: Salary and stock options: Merck & Co., Inc. R. Salgado: Advisory board member: Roche; Research funding: Puma; Travel expenses: Roche. All other authors have declared no conflicts of interest.