KRAS G12C Inhibitors: From Single Drug Competition to Combination Therapy Breakthrough

As the first oncogene discovered in human history, RAS gene mutation is associated with about 20% of tumors

The KRAS gene mutation is the most common type of RAS gene mutation, accounting for about 85%

Although this carcinogenic mechanism was discovered by scientists as early as 30 years ago, the road to becoming a drug has been quite bumpy

Therefore, KRAS was once considered a non-drugable target

Amgen broke the saying that KRAS targets cannot be medicines, and also made global pharmaceutical companies restless, and everyone followed up the research and development of KRAS G12C inhibitors

Recently, at the 2022 AACR Annual Meeting, a number of pharmaceutical companies announced the latest results of their investigational therapies targeting the KRAS pathway

/ 01 /

The latter come first,

Can Amgen stand up to the challenge?

At this AACR conference, the pioneer Amgen released the latest data

Amgen announced two years of long-term follow-up data on sotorasib in KRAS G12C-mutated non-small cell patients

In addition, the median progression-free survival of patients was 6.

On the target of KRAS, the latecomers are also not to be underestimated

At the AACR conference, Novartis announced preliminary results from a Phase 1/2 clinical trial of its KRAS G12C inhibitor JDQ443

Of course, the sample size for this result was small

Among the latecomers, there are also Chinese pharmaceutical companies

In a phase 1 clinical study of 22 patients with KRAS G12C-mutated advanced or metastatic solid tumors, D-1553 was well tolerated in 22 patients, with no dose-limiting toxicities observed; evaluable in 21 patients Among the patients with curative effect, the objective response rate was 19.

The efficacy data of D-1553 for non-small cell carcinoma are relatively more objective

/ 02 /

Mirati unveiled SOS1 inhibitor structure,

Combination therapy breaks out

At the AACR conference, Mirati is naturally indispensable

In the KRAS G12C inhibitor competition, Mirati's progress is second only to Amgen
.
At present, the KRAS G12C inhibitor Adagrasib developed by it has submitted a marketing application for the treatment of non-small cell carcinoma patients with KRAS G12C mutation and who have received at least one prior systemic therapy
.

The KRAS G12C inhibitor introduced by Zai Lab is Adagrasib from Mirati
.

At this conference, Mirati announced the chemical structure of its Adagrasib partner SOS1 inhibitor MRTX0902
.

The SOS1 protein can convert the inactive KRAS protein into an active state
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By inhibiting the SOS1 protein, MRTX0902 keeps KRAS inactive for longer
.

Adagrasib binds to the inactive KRAS G12C mutant
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In combination with MRTX0902, Adagrasib may bind more KRAS G12C mutants, thereby improving the ultimate efficacy
.

In fact, KRAS G12C inhibitors have already entered the era of combination therapy
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Not only Mirati, but other pharmaceutical companies have also launched the exploration of combination therapy, mainly in combination with upstream and downstream pathways or immune checkpoint inhibitors
.

The partners of Amgen sotorasib include Merck's K drug and Revolution Medicines' SHP2 inhibitor; Novartis JDQ443 is also used in combination with SHP2 inhibitor TNO155, or PD-1 (BeiGene's Tislelizhu)
.

After breaking the history of being undruggable, KRAS G12C inhibitors are ushering in a research and development boom, and the competition is becoming more and more fierce
.
If domestic pharmaceutical companies want to break through, they obviously need to do more
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