[vqtilley]

Thanks to everyone and especially Rhondalea for your kind advice on accessing the 2015 Kalsi review article on Kadcyla and brain mets. Prowling around Google I was able to access it free via Research Gate (RG). You have to be a published scholar to get on RG -- any academic field, apparently, because mine isn't medical -- but once you're there, Kalsi et al have posted their article on their RG page and it's downloadable. I wish I could provide a link but it's firewalled. Here are some highlights. Note: This article is based on a single case study of a 28-year old woman with BM who progressed on everything until she took TDM-1, but includes a short background summary of research to date including EMILIA. One important bit here is the possibility of avoiding WBRT and the very low incidence of new brain mets while on TDM-1. Another is the suggestion that TDM-1 without the more toxic lapatinib and capecetibine, although that combo is powerful, appears to be efficacious: only 2% of patients on TDM-1 with BM at baseline developed CNS disease. BTW, I've gone back on letrozole due to its relatively strong BBB penetration and unclear early MRI signals of leptomeningeal spinal disease - hope the combo works.

Brain Metastasis and Response to Ado-Trastuzumab Emtansine: A Case Report and Literature Review
Richa Kalsi,1 Steven Feigenberg,2 Young Kwok,2 Katherine Tkaczuk,1
Minesh Mehta,2 Saranya Chumsri3

... "Preclinical studies showed that lapatinib can penetrate the BBB and significantly decreased phosphorylation of HER2 in metastatic CNS lesions.10 Based on these results, a number of prospective clinical trials were conducted to evaluate the efficacy of
lapatinib in controlling BM (summarized in Table 1).11-17 Despite the promising preclinical studies, lapatinib monotherapy seems to have only modest CNS activity. In a large multicenter phase II study,12 there was only a 6% CNS objective response rate (ORR) with single-agent lapatinib. In the extension part of this study, the
addition of capecitabine to lapatinib increased the CNS ORR to 20%. Subsequent studies confirmed the CNS activity of this regimen with the CNS ORR ranging from 18% to 66% (Table 1). Based on the promising activity of this combination and the fact that WBRT is associated with the risk of neurocognitive dysfunction, in the LANDSCAPE trial upfront treatment with lapatinib and capecitabine before WBRT was evaluated.16 Interestingly, almost two thirds (65.9%) of patients had a CNS objective response to lapatinib
and capecitabine without WBRT. The median time to progression was 5.5 months for systemic and CNS progression.

... "More recently, the retrospective analysis of the EMILIA trial, a phase III trial comparing T-DM1 with lapatinib and capecitabine, showed that the incidence of BM was
quite low in both treatment arms (1.8% in T-DM1 and 0.6% in lapatinib and capecitabine). Furthermore, among 95 patients with BM at baseline, only 2% who received T-DM1 and 1.6% who received lapatinib and capecitabine developed CNS progressive disease during the study. The median PFS in patients with BM at baseline was similar in both groups (5.9 months in the T-DM1 and 5.7 months in the lapatinib group; hazard ratio [HR], 1.0; P ¼ .9998). Similar to the result of the whole trial,5 the median OS was also significantly longer in patients with baseline BM treated with T-DM1 compared with lapatinib and capecitabine (26.8 vs. 12.9 months; HR, 0.382; P ¼ .0081).26

"Despite disease progression during multiple lines of systemic therapies including trastuzumab, pertuzumab, and lapatinib, our patient had a striking CNS response with T-DM1. A similar phenomenon has been reported in another case that described a patient who also showed significant CNS response to single-agent T-DM1.27 Based on the striking CNS response seen in these patients and the retrospective analysis from the EMILIA trial, it seems that T-DM1 might have the ability to cross the BBB and effectively target BM." ...

CONCLUSION

"Although targeted therapies such as combinations of lapatinib or trastuzumab have demonstrated some efficacy in the treatment of BM, the options available for these patients remain limited. This further emphasizes the immediate need to explore other options and conduct further preclinical and clinical research in this field. In addition, patients with progressive CNS metastases face diminished quality of life due to neurocognitive and/or neurologic decline. T-DM1 appears to show CNS and non-CNS activity and has demonstrated better tolerability. With its favorable side effect profile5
and known efficacy in the treatment of systemic metastasis of HER2þ breast cancer, a more rigorous investigation of its activity in the CNS is necessary. Moreover, the combination of these systemic therapies with stereotactic radiosurgery as a way to safely defer WBRT should also be further evaluated as a way to potentially improve quality of life by minimizing neurocognitive dysfunction. Finally, even in patients who require WBRT, combination approaches using these BBB-penetrating anti-HER2 therapies need to be investigated further."