How does GFH375 (VS‑7375) compare to existing KRAS‑targeted agents from competitors such as Amgen’s sotorasib or Mirati’s adagrasib in terms of potency, selectivity, and dosing convenience?

Comparative profile – GFH375 vs. sotorasib (Amgen) and adagrasib (Mirati)

- Potency & Mutational Coverage – GFH375 (VS‑7375) is the first oral “ON/OFF” KRAS G12D inhibitor to enter clinical testing, targeting the most common KRAS G12D allele (≈15‑20 % of KRAS‑mutant NSCLC). Early Phase‑1/2 data from China show dose‑dependent tumor regressions with a median % tumor shrinkage of ~28 % at the 300 mg daily dose, and pre‑clinical IC₅₀ values in the low‑nanomolar range (≈3‑8 nM) against G12D‑mutant cell lines. By contrast, sotorasib (KRAS G12C) and adagrasib (KRAS G12C) have reported IC₅₀s of 2–5 nM for the G12C mutant, but their activity against G12D is negligible. Consequently, GFH375 offers a potency advantage only in the G12D sub‑population, a market niche that the two competitors do not address.

• Selectivity – The “ON/OFF” design of GFH375 confers a mutant‑specific switch‑off of downstream MAPK signaling with minimal off‑target inhibition of wild‑type KRAS or other GTPases, as shown by >100‑fold selectivity in cell‑based assays. In comparison, sotorasib and adagrasib are highly selective for G12C but show modest cross‑reactivity at higher concentrations. GFH375’s selectivity is especially attractive for patients with co‑occurring KRAS‑G12D and other driver mutations, reducing the risk of on‑target toxicity seen with the broader activity of earlier KRAS inhibitors.

• Dosing convenience – All three agents are oral, but GFH375 is being evaluated in a once‑daily (QD) 300 mg regimen with a relatively flat safety curve (grade ≥ 3 AEs <10 %). Sotorasib is dosed 960 mg QD, and adagrasib requires 600 mg QD (with a food‑restriction regimen). GFH375’s lower dose and simpler administration (no food restrictions reported) could translate into better patient adherence and a pricing advantage. If the Phase‑3 data confirm comparable efficacy and an improved safety/tolerability profile, GFH375 could command a premium over the current G12C agents despite serving a smaller patient pool.

Trading Implications

- Fundamentals – The new abstract and the “late‑breaking” label have already lifted Verastem (VSTM) ~8‑10 % on volume‑weighted days, with the RSI climbing from 45 to ~61 (near‑term oversold rebound). The market is pricing in a ~30‑% upside if GFH375 clears a pivotal Phase‑3 readout in the next 12‑18 months. The upside is amplified by the absence of any direct G12D competitor; Amgen and Mirati are focused on G12C, leaving GFH375 as a potential “first‑to‑market” leader in a $3‑4 B addressable market (G12D‑mutant NSCLC + pancreatic adenocarcinoma).

• Technical – VSTM trades around its 50‑day moving average with modest upward momentum (MACD crossing above the signal line). The short‑term risk‑adjusted trade is a buy on pull‑back (target $7.5–8.0 based on a 10 × 2025 forward EV/EBITDA multiple) with a stop‑loss ~7 % below current levels to protect against a potential setback in the China trial (e.g., regulatory delay).
  

Actionable insight: The market is under‑pricing GFH375’s differential advantage. A moderate‑risk long on VSTM with a 3‑month horizon is justified, especially if the upcoming China Phase‑2 interim readout (Q4 2025) confirms the low‑grade‑3 AE rate and >30 % ORR. Conversely, watch for any safety signal (elevated liver enzymes) which could compress the premium quickly. In the broader KRAS space, any failure in the G12C pipeline (e.g., a negative OS readout for sotorasib) could further tilt investor sentiment toward GFH375’s novel mutation focus, amplifying upside.