Pembrolizumab Demonstrates Antitumor Activity in High TMB Metastatic Breast Cancer


Findings from a cohort of the phase II Targeted Agent and Profiling Utilization Registry (TAPUR) basket study revealed that heavily pretreated patients with metastatic breast cancer and high mutational burden benefited from pembrolizumab monotherapy. 

Ajjai S. Alva, MBBS

Ajjai S. Alva, MBBS

Ajjai S. Alva, MBBS

Findings from a cohort of the phase II Targeted Agent and Profiling Utilization Registry (TAPUR) basket study revealed that heavily pretreated patients with metastatic breast cancer and high mutational burden (TMB) benefited from pembrolizumab (Keytruda) monotherapy. 

Among the 28 patients with advanced breast cancer who had 9 to 37 mutations/megabase (Muts/Mb) by the FoundationOne genomic test (or who had a high TMB using another assay) and who received pembrolizumab, 2 mg/kg over 30 minutes or 200 mg IV every 3 weeks, as part of TAPUR, 6 patients (21%) had an objective response (OR) and 4 others had stable disease at 16+ weeks, for a disease control (DC) rate of 37%. The median progression-free survival was 10.6 weeks and the median overall survival was 31.6 weeks.

“Pembrolizumab was very impressive as monotherapy,” said Ajjai S. Alva, MBBS, who presented the data at the 2019 ASCO Annual Meeting. “This study shows that [patients with] biomarkers like high TMB could benefit from single agent anti—PD-1 therapy.”

High TMB is an emerging predictive biomarker for checkpoint inhibitor therapy, “but to be honest, we do not have a perfect biomarker,” said Alva, medical oncologist, University of Michigan, Ann Arbor. “PD-L1 initially came out and it has its flaws. TMB also has a lot of flaws because it does not account for the host immune response. We do need other factors to weigh in to come up with an integrated biomarker.” TMB also assigns equal weight to tumor mutations and doesn’t consider neoantigen quality, he added.

TAPUR is a single-arm nonrandomized study that is studying FDA-approved targeted therapies in patients with advanced cancers. Each cohort includes participants with the same tumor type.

Patients eligible for TAPUR had advanced cancer, no standard treatment options, an ECOG performance status of 0 or 1, measurable disease, and acceptable organ function. Treatment was assigned according to a prespecified protocol that matched the treatment to the specific genomic alteration. In the subset of 28 patients with metastatic breast cancer who were assigned to treatment with pembrolizumab monotherapy, the genomic test performed was FoundationOne in 20 patients (71%) and Caris MiProfile in 1 (4%). In 7 patients (25%), the genomic alteration was determined by an in-house laboratory genomic test.

“In the 7 patients who had house-level assays, the cutoff for high TMB is not the same as with FoundationOne, so their cases had to go to a Molecular Tumor Board within the study, made up of genomics experts,” Alva said.

In TAPUR, if ≥2 of 10 patients in stage 1 have DC, OR, or stable disease at 16 weeks, an additional 18 patients are enrolled. If ≥7 of 28 patients have DC, the drug is considered worthy of further study.

Median age of the patients in this cohort was 63 years. Seven percent had received 2 prior systemic treatment regimens and 93% received ≥3 prior systemic regimens. Eight patients received pembrolizumab at 2 mg/kg and 20 were treated with 200 mg IV. The time on treatment in the 10 patients with OR or SD ranged from 17 to 80+ weeks; treatment is ongoing in 2 patients.

The ability of high TMB to predict better response to immune checkpoint inhibitor therapy cannot be ascertained from this study as it lacked a control group, Alva said. “We don’t have a low TMB cohort,” he said. “These were all patients who had high TMB as defined by their assay.” No relationship was observed between the number of muts/mb and PFS or OS.

A total of 6 adverse events/serious adverse events experienced by 4 patients were deemed to be at least possibly related to pembrolizumab. The 3 serious adverse events, all grade 3, were weight loss, hypoalbuminuria, and hyponatremia.

Mutational burden is a proxy for neoantigen load or possibly a mediator of innate cellular inflammation due to a large number of misfolded proteins within the cells, said discussant Justin Balko, PharmD, PhD, assistant professor of cancer biology, Vanderbilt University Medical Center, Nashville.

The 21% OR “is similar to what we’ve seen in some of the early single-agent pembrolizumab studies in triple-negative breast cancer,” Balko said. “This study population was essentially the highest 10% of TMB patients in metastatic breast cancer, and although we don’t know the hormone receptor status, we do know from previous trials that hormone receptor-positive patients in the metastatic setting were poorly responsive to immunotherapies. If a number of these patients were hormone receptor-positive that were in the responding group, then perhaps high TMB among that population could help to define some new patients who could be treated with immunotherapy.”


Alva AS, Mangat PK, Garrett-Mayer E, et al. Pembrolizumab (P) in patients (pts) with metastatic breast cancer (MBC) with high tumor mutational burden (HTMB): results from the targeted agent and profiling utilization registry (TAPUR) study.J Clin Oncol.2019;37(suppl; abstr 1014).

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