PRECIOUS: Pertuzumab Re-treatment Improved OS in HER2-Positive LA/MBC in a Phase 3 Trial, but Did Treatment Imbalances Impact the Outcomes?

Previous reports of the phase 3, open-label, randomized PRECIOUS (NCT02514681) trial demonstrated a modest improvement in investigator-assessed progression-free survival (PFS) with pertuzumab re-treatment in combination with trastuzumab plus physician’s choice chemotherapy (PTC) compared with trastuzumab plus chemotherapy (TC) alone in patients with HER2-positive locally advanced/metastatic breast cancer (LA/MBC) who had previously received pertuzumab-containing regimens. At the ASCO 2023 annual meeting, updated overall survival (OS) data were presented from a median follow-up of 27.4 months.

The study enrolled patients with HER2-positive LA/MBC who were previously treated with pertuzumab-containing regimens as first- or second-line treatment. Eligible patients were randomly assigned 1:1 to receive PTC or TC therapy; patient stratification was by estrogen receptor status, previous treatment duration of pertuzumab, number of previous chemotherapy regimens, and presence or absence of visceral metastasis. The primary end point was investigator-assessed PFS. The key secondary end points included OS, independent reviewer–assessed PFS, and safety. Data cutoff was December 31, 2021.

A total of 217 of 219 enrolled patients were included in the intent-to-treat population; of these, 108 received PTC and 109 received TC. At a median follow-up of 27.4 months, the PTC regimen was associated with a significantly longer median OS compared with TC (36.2 vs 26.5 months; hazard ratio [HR]=0.73; log-rank test P=.0323), which extended to all subgroups tested (estrogen receptor status, visceral metastases, number of previous chemotherapy regimens). Similarly, investigator-assessed PFS was also significantly prolonged with the PTC regimen compared with TC (5.5 vs 4.2 months; HR=0.81; stratified log-rank test P=.019). In the updated safety analysis, no new safety signals in the 2 groups were noted, with similar rates of serious adverse event rate (19.0% vs 23.1%).

Despite the significant survival benefits reported, identified differences among the PTC and TC cohorts may have impacted the outcomes, including chemotherapy received and key anti-HER2 treatment received after progression. More patients in the PTC cohort received eribulin than in the TC cohort (58.3% vs 43.1%, respectively); notably, the EMBRACE trial demonstrated an improved survival benefit with eribulin over other chemotherapies (NCT00388726). In addition, more patients in the PTC cohort received trastuzumab deruxtecan than in the TC cohort (26.9% vs 18.3%, respectively); trastuzumab deruxtecan has demonstrated a better survival benefit in HER2-positive metastatic breast cancer compared with other agents. It is possible that the observed improvement in overall survival may be due to a superior chemotherapy regimen during and after study participation in the experimental arm.

This phase 3 study addresses a clinically relevant question; however, potential imbalances in chemotherapy during and after study treatment may have impacted OS. Additional research is needed to identify patients who may benefit from retreatment with pertuzumab. These findings warrant further analysis of patient characteristics associated with prolonged survival and the impact of subsequent therapies on long-term outcomes in clinical trials.

Source:

Yamamoto Y, Iwata H, Takahashi M, et al. Pertuzumab retreatment in patients with HER2-positive locally advanced/metastatic breast cancer: overall survival results of a phase III randomized trial (JBCRG-M05: PRECIOUS). Abstract presented at: ASCO Annual Meeting, June 2-6, 2023; Chicago, IL. Abstract 1015.