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Did some work on $VSTM, and just wanted to share some high level thoughts and questions from my thesis (I'm long $VSTM, spoiler alert) but have a fair amount of healthy skepticism too. 11 tweets, read it and weep... (1/11)
The story begins with messy and scattered clinical data from #MEKi's (trametinib and selumetinib), defactinib (FAKi) and #CH5126766 (a dual RAF/MEKi) across multiple studies in #KRAS mutant NSCLC. I'll start with the old (and pretty bad) defactinib data. (2/11)
2% ORR (1/53). A mere 28% of patients reaching 12 week PFS. 2 patients with grade 5 respiratory AEs. At first, I scratched my head as to why this data alone didn't deter the big institutional investors from doing more diligence full stop, so I followed them into the void. (3/11)
Preclinical data suggests that #MEK inhibition induces activation of the #FAK pathway, so I guess that rationalizes adding defactinib into the mix. Maybe it's one of "those" (one works with the other, like how a car needs a driver). The dismal preclinical data aside... (4/11)
Read a ton of papers, and I actually convinced myself that the missing piece of the equation is RAF, and it honestly might be! The hard part was finding RAFi data (anything but sorafenib for fucks sake) to compare with data from #Chugai's CH5126766. (5/11)
So onto the RAF/MEK piece of the puzzle and the Chugai data: 30% ORR (3/10). Now that's not bad, especially when comparing cross-trial with selumetinib+docetaxel (37% ORR) and trametinib mono (12% ORR). There's even some OS and PFS data from these dinosaurs... (6/11)
Selum+docetaxel showed an OS of 9.4 months and PFS of 5.3, while trametinib showed an OS of 8 months and PFS of 2.7 months. It's unlikely that the data we're getting from $VSTM on Monday has OS data, but I'd use these anecdotal data as the bar. (7/11)
The safety profile for CH5126766 is limited though–– a Ph1 study reports all grade AEs: 94% rash, 56% elevated CPK, and 52% diarrhea. I'd say these aren't differentiated from the neutropenia (67% grades 3/4) with selum+docetaxel. (8/11)
Where does the leave us? A jumble of kinda shitty clinical data from various drugs that are trying to hold up at least a 45% ORR. Nevertheless, I am more excited by pan-RAS and novel approaches like the one $VSTM is taking than G12Ci's $MRTX (short) and $AMGN's G12Ci's. (9/11)
But when it comes down to it, I think there is intriguing preclinical evidence and enough mechanistic rational to support the combination of defactinib and CH5126766. The biggest risk is toxicity –– the 2 grade 5 AE's defactinib saw in early trials is worrisome. (10/11)
