Pembrolizumab in Patients With Metastatic Breast Cancer With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study

Abstract

PURPOSE The TAPUR Study is a phase II basket trial that aims to identify signals of antitumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known to be drug targets. Results in a cohort of patients with metastatic breast cancer (mBC) with high tumor mutational burden (HTMB) treated with pembrolizumab are reported. METHODS Patients with advanced mBC received standard doses of either 2 mg/kg or 200 mg infusions of pembrolizumab every 3 weeks. Simon's two-stage design was used with a primary study end point of disease control (DC) defined as objective response or stable disease of at least 16 weeks duration. If two or more patients in stage I achieved DC, the cohort would enroll 18 additional patients in stage II. Secondary end points include progression-free survival (PFS), overall survival, and safety. RESULTS Twenty-eight patients were enrolled from October 2016 to July 2018. All patients' tumors had HTMB ranging from 9 to 37 mutations/megabase. DC and objective response were noted in 37% (95% CI, 21 to 50) and 21% of patients (95% CI, 8 to 41), respectively. Median PFS was 10.6 weeks (95% CI, 7.7 to 21.1); median overall survival was 30.6 weeks (95% CI, 18.3 to 103.3). No relationship was observed between PFS and tumor mutational burden. Five patients experienced ≥ 1 serious adverse event or grade 3 adverse event at least possibly related to pembrolizumab consistent with the product label. CONCLUSION Pembrolizumab monotherapy has antitumor activity in heavily pretreated patients with mBC characterized by HTMB. Our findings support the recent US Food and Drug Administration approval of pembrolizumab for treatment of patients with unresectable or metastatic solid tumors with HTMB without alternative treatment options.

Case Report: A Case Study Documenting the Activity of Atezolizumab in a PD-L1-Negative Triple-Negative Breast Cancer

“…Currently, three biomarkers have been clinically validated as predictors of response to immune checkpoint blockade in TNBC [i.e., PD-L1 (2)] and across cancer types (i.e., TMB (3,14) and mismatch repair deficiency (15). Indeed, the immunotherapy drug pembrolizumab for the treatment of patients with TMB-high tumors is approved by the Food and Drug Administration (FDA) (14).…”

“…In this context, immunotherapy with atezolizumab, an anti-PD-L1 drug antibody, has been approved for PD-L1-positive (PD-L1+) (i.e., ≥1% PD-L1+ tumor-infiltrating immune cells) advanced TNBC in combination with nab-paclitaxel (2). On the other side, activity of pembrolizumab monotherapy in patients with pretreated metastatic breast cancer with high TMB has recently been reported (3). However, no activity of immune checkpoint inhibitors in PD-L1-negative TNBC has been observed to date, and the predictive value of TMB beyond PD-L1 expression is still unknown.…”

Clinical Progress of PD-1/L1 Inhibitors in Breast Cancer Immunotherapy

“…Standardization of detection assays is another challenge of precisely guiding the prescription of immunotherapy. Studies have shown that high tumor mutation burden (TMB) can predict the efficacy of breast cancer immunotherapy ( 76 , 77 ), but there is no uniform standard for TMB threshold. Although there are some discoveries in biomarker exploration currently, and PD-L1 is recognized, it is still insufficient for tumor microenvironment and biomarker research.…”

Predictive Biomarkers of Immune Checkpoint Inhibitor Response in Breast Cancer: Looking beyond Tumoral PD-L1

“…This trend was interestingly most notable in the ER+ subtype [ 18 ]. In contrast, the TAPUR trial included 28 breast cancer patients with high TMB (≥9 mutations per megabase) and showed an objective response rate of 21%, but subgroup analysis did not demonstrate that high TMB was a positive prognostic biomarker for treatment with ICIs [ 19 ]. Notably, the study was not powered to detect an association between TMB and progression-free survival (PFS).…”