T-Cell–Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028

Abstract

PURPOSE Biomarkers that can predict response to anti–programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell–inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors. METHODS KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1–positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell–inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points. RESULTS ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell–inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports. CONCLUSION A T-cell–-inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti–PD-1 therapies across a broad spectrum of cancers.

Ultraviolet light‐related DNA damage mutation signature distinguishes cutaneous from mucosal or other origin for head and neck squamous cell carcinoma of unknown primary site

“…Recently, it has been proposed that either tumor mutational burden or PD‐L1 expression could be used for selecting patients with cutaneous or mucosal SCC most likely to respond to immunotherapy. Clinical trial subgroup analyses have suggested that these biomarkers are associated with improved response and survival in patients with mucosal SCC . Tumor mutational burden and PD‐L1 expression level are also both under active investigation as biomarkers of response to immunotherapy in other cancers such as lung cancers …”

“…Clinical trial subgroup analyses have suggested that these biomarkers are associated with improved response and survival in patients with mucosal SCC. 17,18 Tumor mutational burden and PD-L1 expression level are also both under active investigation as biomarkers of response to immunotherapy in other cancers such as lung cancers. 19,20 4 | CONCLUSIONS Differentiation of HNSCCUP origin from a cutaneous vs mucosal vs other primary site is a diagnostic challenge.…”

Incorporation of molecular characteristics into endometrial cancer management

“…In recent years several targetable pathways in the context of molecular EC subgroups have been investigated, resulting in novel treatment strategies with potential clinical benefit. POLE mut and MMRd EC, due to their high mutational burden, obtain high levels of neoantigens and TILs, making them attractive candidates for immunotherapy such as anti‐PD1 immune check‐point blockade . Despite this theoretical argument, the excellent clinical outcomes for patients with POLE mut EC under current treatment regimens (independent of stage), however, argues against the rationale to the use of immunotherapy for this subpopulation.…”

“…POLEmut and MMRd EC, due to their high mutational burden, obtain high levels of neoantigens and TILs, making them attractive candidates for immunotherapy such as anti-PD1 immune checkpoint blockade. 32,33,[51][52][53][54][55][56][57] Despite this theoretical argument, the excellent clinical outcomes for patients with POLEmut EC under current treatment regimens (independent of stage), however, argues against the rationale to the use of immunotherapy for this subpopulation. For MMRd EC, particularly when recurrent or in advanced metastatic stage (FIGO stage >III), immune check-point inhibition may be an attractive option.…”

Molecular characterization of clinical responses to PD‐1/PD‐L1 inhibitors in non‐small cell lung cancer: Predictive value of multidimensional immunomarker detection for the efficacy of PD‐1 inhibitors in Chinese patients

“…In KEYNOTE‐028, a study of pembrolizumab treatment across 20 cancer types, higher T‐cell‐inflamed gene‐expression profile (GEP), PD‐L1 expression, and/or TMB were associated with higher response rates and longer PFS. The subgroup of patients with tumors that had both high TMB and high inflammatory markers (GEP or PD‐L1) had the highest likelihood of response …”