In patients with HER-2 positive breast cancer on pertuzumab/trastuzumab with newly developed asymptomatic brain metastases only, do you wait 3 weeks after administration of the targeted therapy to deliver SRS?
In a recently published study from Italy, Ippolito et al., PMID 35053467 a total of 10 patients with 32 HER2+ breast cancer brain metastases were treated with concurrent fSRT (27 Gy in 3 fractions) and Pertuzumab. Necrosis was reported in only 1 of the 32 treated lesions. The study is small but the authors conclude that concurrent use of fSRT + Trastuzumab appeared to be safe.
In addition, reports on concurrent use outside of the CNS, support the notion that concurrent irradiation + Pertuzumab is feasible and well tolerated, including in cases of locoregional breast irradiation. Debbi et al., PMID 37190205
As such, I would not wait 3 weeks to administer SRS.
We don’t hold for herceptin and pertuzumab for SRS but do hold for T-DM1 as it has increased risk of radionecrosis.
Several retrospective studies have shown the good tolerance of concomitant radiotherapy with trastuzumab and pertuzumab either in loco-regional or distant metastatic disease. However, given the underlying mechanism of action, the use of antibody-drug conjugates of trastuzumab (trastuzumab emtansine, trastuzumab deruxtecan) in this setting, may need some caution. The safety of the combination of a tyrosine kinase inhibitor (lapatinib, tucatinib) and radiation remains under studied. The available evidence suggests that checkpoint inhibitors can be safely administrated with radiation. Debbi et al., PMID 37190205
Specific to the posed question, in a retrospective study of 10 patients with 32 HER2+ breast cancer brain metastases treated with concurrent stereotactic brain radiotherapy and trastuzumab and pertuzumab, no local progression was observed with an overall response rate of 68.7%. Only one patient developed asymptomatic radionecrosis. The median time to brain metastasis occurrence was 15.6 (range: 1–40.5 months). Distant intracranial failure occurred in 4/10 patients (40.0%). Overall median survival was 33.9 months (95%CI 24.1–43.6). The mean duration of trastuzumab and pertuzumab treatment was 27.9 months (range: 10.1–53.7 months). (Ippolito et al., PMID 35053467)
In another retrospective but largest study of its kind, ninety-eight patients with brain metastases treated with stereotactic brain radiotherapy and antibody-drug conjugates, trastuzumab emtansine, trastuzumab deruxtecan, or sacituzumab govitecan. The 24-month cumulative incidence of symptomatic radiation necrosis for the entire cohort was 8.5% (range, 6.2%-11.0%). Concurrent stereotactic radiation and antibody-drug conjugate use (defined as radiation was delivered 7 or fewer days before, or 21 or fewer days after antibody-drug conjugates) was associated with a higher risk of symptomatic radiation necrosis. The risk was modest for small brain metastases receiving their first course of stereotactic radiation therapy but was substantial for larger lesions and re-irradiated brain metastases. (Lebow et al., PMID 37883079, Copur MS JAMA Oncol. 2023 Online Commentary)
While the optimization of the timing of the combination therapy still needs further research and demonstration, and the possibility of radiation necrosis cannot be ignored, I would not wait 3 weeks to deliver stereotactic radiation therapy for the patients posed in the question with newly developed asymptomatic brain metastases. For patients who are on antibody-drug conjugates with previously radiated, and/or large lesions, I would possibly wait for 3 half-lives of the drug. (Drago et al., PMID 33558752)