LBA6 - A phase II, single arm, open label, Simon two-stage study of pembrolizumab in metastatic HER2-negative breast cancer patients: Evaluation of impact of germline variants in APOBEC3B (AUROR)

Background

A common germline deletion polymorphism in the APOBEC3B cytosine deaminase gene [A3Bdel] occurs more frequently in Asian women (45% heterozygous and 15% homozygous carriers) compared to in Caucasian women (15% and 4% respectively). Carriers are more likely to develop breast cancer, and cancers in carriers are more likely to have a hypermutator phenotype (with C>T transitions) and to be immune-enriched. In this clinical trial, we aimed to evaluate the response of A3Bdel carriers with metastatic HER2-negative breast cancer patients to checkpoint immunotherapy.

Methods

Using DNA extracted from peripheral blood, germline APOBEC3B polymorphism status was determined using single tube PCR assay using one forward and two reverse primers flanking the deletion. In total, 146 patients were screened, and 92 patients (63%) were found to be either homozygous or heterozygous carriers. 44 subjects who received >= 1 but <=3 lines of therapy in a metastatic setting were enrolled and given pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W), with Objective Response Rate (ORR) using RECIST 1.1 as the primary study endpoint.

Results

The median age of patients was 58.1 years (range, 32.1–82.9), of whom 75.0% were Chinese, 18.2% Malay, 4.5% Indian and 2.3% other ethnicity, and 31 patients had ECOG 0 and 13 had ECOG 1. The median number of lines of therapy received by the patients were two lines (range, 1–3). The ORR was 20.4 % (95% CI: 8.5 – 32.4) in 40 evaluable patients, which included one complete response and eight partial responses, as determined by RECIST 1.1.. Of these 9 patients, at the time of this analysis, 3 are still ongoing treatment and 6 had a median duration of response of 8.8 months (range: 2.1 – 32.4). The median OS was 15.4 months (95% CI: 11.7–26.5), with a 6-month and 1-year OS rate of 81.1% (95% CI: 70.1–93.9) and 62.0% (95% CI: 47.7–80.5), respectively. Notably, whereas responses to checkpoint immunotherapy have been reported to be low in ER+ patients, in A3B carriers, we found similar trends in OS, PFS and ORR in both ER+ and ER- patients, which warrants further analysis. The treatment was well tolerated by patients, with 13 out of 40 subjects experiencing SAEs, of which only 1 (colitis) was related to the investigational product.

Conclusions

Single agent pembrolizumab demonstrated promising anti-tumour activity in germline A3Bdel carriers, who constitute almost two-thirds of Asian patients.

Clinical trial identification

NCT03989089.

Editorial acknowledgement

Legal entity responsible for the study

University Malaya Medical Centre.

Funding

Merck Sharp & Dohme.

Disclosure

All authors have declared no conflicts of interest.