AACR: Verastem, Quanta and Frontier demonstrate KRAS inhibitors' potential in preclinical data

Verastem Oncology, Frontier Medicines, Quanta Therapeutics and more shared preclinical updates at the American Association for Cancer Research’s (AACR's) annual meeting in San Diego in early April, adding to the ever-growing list of companies vying to bring forth therapies against the once-“undruggable” target. 

Verastem presented a poster showing that an oral KRAS G12D inhibitor called GFH375/VS-7375, which the company is developing with partner GenFleet Therapeutics, is effective against pancreatic and colorectal cancers in mice. The drug works by targeting the KRAS protein in both its “on” and “off” states, meaning when the protein contributes to cell proliferation and when it doesn’t. 

Other KRAS G12D inhibitors with preclinical updates at the conference included Revolution Medicines’ clinical-stage RMC-9805, which works by inhibiting the KRAS protein in its “on” state. Revolution researchers presented data showing that as a monotherapy, the drug can suppress tumor growth in animal models of pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). RMC-9805 is currently being studied in a phase 1 clinical trial involving patients with NSCLC, PDAC, colorectal cancer or other solid tumors. 

Looking beyond G12D, Quanta Therapeutics presented a poster with data showing that its oral drug QTX3544, which targets KRAS G12V, suppressed tumor growth in mouse models of gastric, pancreatic, lung and ovarian cancers. Frontier Medicines used the AACR event to present a poster with new data showing that its KRAS G12C inhibitor FMC-376 decreased the size of tumors in mouse models of NSCLC and colorectal cancer, which were derived from the cells of patients who had already been treated with KRAS inhibitors. Combining FMC-376 with a PD-1 inhibitor also boosted the efficacy of the PD-1 inhibitor in mouse models of lung cancer, which were less likely to develop central nervous system metastases.

“We really pushed FMC-376 preclinically to better understand its ability to overcome common resistance mechanisms that have plagued single-acting KRAS inhibitors and limited their ability to provide meaningful and durable benefits to people with KRAS G12C cancers,” Frontier's chief medical officer Andrew Krivoshik, M.D., Ph.D., said in a press release

Like Verastem’s GFH375/VS-7375, Frontier's FMC-376 acts on KRAS in both its “on” and “off” states, but for a different mutation. The two FDA-approved KRAS G12C inhibitors, Amgen’s Lumakras and Mirati Therapeutics' Krazati, act on the molecule only in its “off” state. So far, FMC-376 has the potential to be a first-in-class drug. 

In other early-stage KRAS news from the conference, scientists from Johns Hopkins University presented data from a phase 1 trial showing that an off-the-shelf cancer vaccine against the six most common KRAS mutations in PDAC generated T cells specific to the mutations in patients with PDAC who also received a combination of Bristol Myers Squibb's immunotherapies Opdivo and Yervoy. 

Editor's note: A previous version of this story also referred to Revolution Medicine's drug RMC-6236 in combination with RMC-9805. The presentation on RMC-6236 was in combination with a different drug and this reference has now been removed from the article.