Relationship between tumor infiltrating lymphocyte (TIL) levels and response to pembrolizumab (pembro) in metastatic triple-negative breast cancer (mTNBC): Results from KEYNOTE-086

Abstract

Background: 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). Methods: 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 þ PR þ 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. Results: 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 meta-static 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 ¼ .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 ¼ .01) and DCR (odds ratio 1.22, 95% CI 1.02-1.46, P ¼ .01). Area under the ROC curve was 0.75 for ORR and 0.69 for DCR. PD-L1 expression significantly correlated with TIL levels (q ¼ 0.4962, P < .001). Conclusions: TIL levels can identify pts with mTNBC with a greater chance of achieving response to pembro monotherapy, particularly in the first-line setting.