When generating the TOC for EPUB, Pandoc understandably strips HTML markup inside headers. It should still account for line breaks, and substitute them with spaces.

When a header is

# First chapter<br/><span class="subtitle">The beginning</span>

its TOC entry should be

First chapter The beginning

which might not be ideal but is unquestionably better than the current output:

First chapterThe beginning

Note that <br/> might exist for presentation purposes (so it is irrelevant whether you agree or not with the above markup being appropriate for subtitles).

In the meantime, this can be worked around by manually adding a space after br which, being a space at the beginning of line, will not render (if I am not mistaken), but Pandoc will still keep it as a separator of words when generating the TOC.