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A Phase I/II clinical trial of PDAC patients with RAS mutations, developed by Targovax, showed increased immune response and extended total survival. Its second-generation vaccine, TG-02, has been used to treat patients with colorectal cancer, but results have not yet been announced. The mRNA vaccine for KRAS mutations has also been in clinical trials and can be used in conjunction with pymzumab.
Future direction
KRAS-G12C alleles gene-specific inhibitors will change the therapeutic prospects of RAS-driven tumors. These inhibitors are expected to be the first treatments for FDA-approved RAS mutant tumors and will be used to treat refractive cancers driven by RAS mutations, such as PDAC, CRC and LUAD. While the development of these inhibitors is exciting, new challenges and problems will arise.
First, each variant in RAS has unique biochemical characteristics that determine the different responses to treatment. For example, using RMC-4550 to suppress SHP2 can effectively treat cells with KRAS G12 mutations and is more effective for KRAS G12C than for KRAS G12D or KRAS G12V. The observation shows that the combination of SHP2 and KRAS-G12C inhibitors will be an effective treatment strategy. When developing combination therapies, it is necessary to understand the requirements of the specific mutant RAS cryptand and the response of inhibitors to these alleles.
Second, tumor types can significantly affect the rate of remission, and the response of THE CRC and PDAC of the RAS mutation to MAPK inhibitors or immunocheckpoint blocking is very small. Early data from the AMG 510 trial showed that CRC was more difficult to treat than LUAD, suggesting that CRC needed to use combination therapy.
Third, from experience, combination therapy is prone to toxic side effects and is less safe. However, Dose-restrictive toxicity has not been observed in AMG 510, and mutant-specific therapies should have limited off-targeting effects. The ilegenic-specific inhibitors (low toxicity) can be used in combination with other inhibitors with greater toxicity without encountering problems observed in the combination of two toxic compounds, as in the case of PI3K and MEK inhibitors.
Overall, the FDA opens fast lanes to RAS Targeted Therapy AMG510, an exciting time that rekindles hope for successful treatment of RAS mutation cancers.
