The approved TRK inhibitor Vitrakvi did not play a big part in Lilly’s $8bn takeout of its maker, Loxo, but the drug is a focus for Bayer, Loxo’s longer-standing partner. The related project LOXO-195 is at least as important for the German group, and clinical results unveiled today at the AACR meeting have underlined its value.
LOXO-195 is also a TRK inhibitor, but has been designed to work in patients who have relapsed on Vitrakvi or Roche’s rival, entrectinib, despite carrying a TRK kinase mutation. The AACR data back the hypothesis that LOXO-195 works in these subjects but not in others who relapse in different ways after first-line TRK therapy.
They come from 29 evaluable post-TRK-inhibitor subjects, derived from a phase I study and US compassionate-use programme. 20 of these patients had some kind of residual TRK mutation, but the rest either did not, or their status was unknown.
The overall remission rate in the 20 TRK mutants was an impressive 45%, said the lead investigator, Dr David Hyman, from Memorial Sloan-Kettering Cancer Center. The one caveat was that the data come from investigator assessment, and have not yet been independently reviewed.
But the results build on case reports, published in Cancer Drug Discovery back in 2017, in just two subjects who had progressed after Vitrakvi and had what is termed a Solvent Front mutation. Both developed partial responses after treatment with LOXO-195, it was reported.
What LOXO-195 did not demonstrate in the results presented at AACR further backs up the hypothesis behind its development. Namely, none of the three subjects with an identified bypass mechanism, meaning that TRK signalling was no longer driving the cancer, responded to LOXO-195.
|LOXO-195 phase I (NCT03215511) & compassionate-use data|
|TRK resistance mutation||20||45%|
|Source: AACR; *3 identified bypass, 1 no identified TRK mutation or bypass alteration, 5 unknown.|
Lilly acquired Loxo earlier this year, largely for its Ret kinase inhibitor LOXO-292. As soon as the deal closed Bayer exercised a change-of-control option, giving the German group full development rights to Vitrakvi and LOXO-195, which it now calls BAY 2731954.
It is interesting that Ignyta, maker of the rival TRK inhibitor entrectinib, also fell prey to a takeover, by Roche, although the focus of this deal was probably not TRK but Ros1, a mutation that Vitrakvi does not target. Entrectinib is now awaiting US approval.
Vitrakvi’s approval made the drug the second to get a green light irrespective of tumour type. Dr Hyman said TRK mutations were responsible for just 0.5% of all US cancer cases, but that many of these responded to Vitrakvi treatment.
He stressed that the AACR data suggested that LOXO-195 could eventually become a meaningful treatment for subjects whose cancers are resistant to first-generation TRK inhibitors. Bayer will no doubt be keen to point out that one such drug is entrectinib.