Current status of drug development targeting KRAS G12C

In a recent ESMO, Amgen disclosed the latest results of the CodeBreaK 200 Phase III trial, which brought some benefits
to the KRAS G12C inhibitor sotorasib for the treatment of advanced and metastatic non-small cell lung cancer (NSCLC) compared to standard chemotherapy.
After a median follow-up of 17.
7 months, Sotorasib resulted in significant improvements in progression-free survival with mPFS of 5.
6 and 4.
5 months, respectively, and objective response rates of 28.
1% and 13.
2%,
respectively.
However, there was no difference in overall survival between the two groups, with mOS of 10.
6 and 11.
3 months, respectively, and even surpassed the experimental group in the chemotherapy group
.
In terms of safety, the incidence of grade 3 TRAE ≥ 33.
1% and 40.
4%, and the incidence of severe TRAE was 10.
7% and 22.
5%,
respectively.

In general, the efficacy advantage of Sotorasib is not significant, but the safety advantage is obvious, which can be described as an oral drug
with better efficacy and safety for patients with advanced/metastatic NSCLC.
Of course, at present, the development of combination regimens for the treatment of KRAS G12C-positive advanced NSCLC patients with KRAS G12C, such as the combination of KRAS G12C and SHP2 inhibitors, the combination of EGFR inhibitors, and the combination of immune checkpoint inhibitors, are expected to shine in the future
.

1.
Introduction to KRAS G12C

KRAS is the most commonly mutated oncogene in human cancer, and KRAS mutations
have been detected in many types of human cancer.
KRAS mutations are commonly found in pancreatic cancer (95%), CRC (40%), NSCLC (25%), and also in thyroid cancer, ovarian cancer, bladder cancer, systemic lupus erythematosus, breast cancer, liver cancer, etc
.
Globally, the incidence of KRAS mutant-positive cancer is on the rise, from 1.
800 million to 2.
009 million between 2016 and 2020, and is expected to increase to 2.
276 million in 2025 and 2.
56 million in 2030
.
Focusing on China, the top three KRAS-positive cancers are lung cancer, colorectal cancer, and pancreatic cancer
.
From 2016 to 2020, the number of major KRAS mutant cancers in China increased from 421,000 to 477,000, and is expected to reach 558,000 in 2025 and 641,000 in 2030
.

Chart: Number of Major KRAS Mutation-Positive Cancers Worldwide (Source: Frost & Sullivan)

KRAS G12C is a single-point mutation with a glycine-cysteine substitute at the 12th codon, accounting for 11.
3% of KRAS mutations, about 5-13% of patients with non-small cell lung cancer, 3% of colorectal cancer patients, and a lower proportion of several other refractory cancer patients carry KRAS G12C mutations
。 According to Frost & Sullivan, the number of major KRAS G12C mutation-positive cancers worldwide increased from 270,000 to 300,000 between 2016 and 2020, and is expected to increase to 341,000 in 2025 and 385,000 in 2030
.

The relationship of KRAS to tumors

Although the patient population of KRAS mutation is large, the research and development of KRAS drugs is not smooth, on the one hand, the binding of KRAS to the substrate GTP is very strong, and the affinity coefficient reaches the piomolar concentration level, which makes it difficult to develop competitive inhibitors that directly target the GTP pocket; On the other hand, KRAS protein lacks ideal small molecule binding pockets, making it difficult to design allosteric inhibitors
with high affinity.
This led to KRAS once being called an "undruggable" target
.

Until 2013, researchers at the University of California, San Francisco discovered that there was a "pocket" on the mutant protein of the KRAS G12C subtype that could bind to small molecule drugs, and this pocket could lock the KRAS G12C mutant into an inactive conformation, thus providing a potential target for inhibiting the activity of the KRAS mutant
.
At this point, the scientific community has finally found the key to cracking KRAS and been able to break through this "undruggable" target
.

2.
KRAS G12C is under research

Currently, only one KRAS G12C inhibitor has been approved for marketing worldwide, Amgen's AMG510 (Sotorasib).

In May 2021, the US FDA conditionally approved AMG510 for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with KRAS-G12C mutations who have received at least one prior systemic therapy
.
At present, no KRAS G12C inhibitor has been approved in China, and there is currently no standard treatment for
KRAS G12C mutated solid tumors.
At present, clinical treatment options include chemotherapy and immunotherapy, but because these treatments do not directly target KRAS G12C targets, the therapeutic effect is limited
.
In general, patients with advanced KRAS G12C mutations have an urgent need
for KRAS G12C inhibitors.

Table: List of KRAS G12C drugs under global research

Source: CDE, ClinicalTrials

(1) AMG510 is the first approved oral inhibitor targeting KRAS G12C, targeting the hidden groove on the surface of KRAS protein, which can irreversibly bind to the KRAS mutant protein Cys 12 and lock it firmly, so that GDP cannot be activated into GTP, thereby preventing the proliferation
of tumor cells.
In May 2021, Amgen's AMG510 (Sotorasib) was approved by the FDA for marketing, breaking the curse of KRAS "undruggable" and indicated for the second-line treatment of non-small cell lung cancer
with KRAS G12C mutation.

In addition to monotherapy, the AMG510 combination regimen is gradually being introduced
.
At the 2022 WCLC, the Phase I.
b CodeBreak 100/101 study of AMG510 and atezolizumab/pembrolizumab showed that 58 previously treated NSCLC patients had an ORR of 29% and mOS of 15.
7 months, but the incidence of G3 TRAE was significantly higher than that of monotherapy, and the problem of liver toxicity was more serious
.

Currently, the trial of AMG510 for the treatment of KRAS G12C colorectal cancer (CRC) is also underway
.
At ASCO 2020, Amgen disclosed phase I data of AMG510 for colorectal cancer, and 42 subjects who had previously received standard treatment regimens received AMG510 treatment, with ORR and disease control rates of 7.
1% and 76.
2%.

At ESMO 2022, Amgen disclosed a Phase I.
b dose-expansion cohort study of AMG501 in combination with panitumab, an EGFR antibody, with an ORR of 30%, a DCR of 90%, and an mPFS of 5.
7m
in 40 patients.
Overall, the response rate of the Sotorasib combination regimen is nearly four times higher than that of the monotherapy regimen, and the combination regimen is worth looking forward to
.

Comments: AMG510, as the first KRAS G12C inhibitor on the market, has obvious first-mover advantages, achieving sales of 139 million US dollars
in the first half of 2022.
However, the efficacy advantage of AMG510 is not very significant, and the phase III OS data of CodeBreak 100 disclosed by ESMO in 2022 does not even have a significant advantage
with chemotherapy.
In terms of the combination regimen, the combination regimen with immune checkpoint inhibitors has obvious efficacy advantages, but the hepatotoxicity is more obvious; Phase II data in combination with EGFR monoclonal antibody are worth looking forward
to.

(2) MRTX-849 (Adagrasib) was designed by Mirati Therapeutics and is similar
in structure to Amgen's AM510.
In the KRAS protein molecule, cysteine and molecular switch II region (S-IIP) near the 12th codon mutation have a small expandable pocket, and MRTX-849 irreversibly binds to Cys 12 in a covalent form, locking the KRAS G12C protein in the "off" state, thereby blocking KRAS signaling
.

For non-small cell lung cancer, 2022ASCO disclosed a registered phase II clinical trial of Adagrasib, which included a total of 116 patients with NSCLC who had previously received platinum-based chemotherapy and anti-PD-1/L1 therapy, and the results showed that the ORR of 112 patients with baseline measurable disease was 43%, DCR was 80%, mPFS was 6.
5 months, and mOS was 12.
6 months
.
The investigators further evaluated the efficacy
of Adgrasib in treated patients with stable CNS metastases.
The intracranial ORR was 33%, including 5 cases of CR (15%) and 6 cases of PR (18%)
.

For colorectal cancer, the phase I/II clinical trial of Adagrasib monotherapy and combination cetuximab was disclosed at ESMO 2022, and the results showed that the objective response rate of Adagrasib monotherapy was 19% (8/43), the disease control rate was 86%, and the mPFS was 5.
6 months
.
In the combined group, the objective response rate of 32 patients was 46%, the disease control rate was 100%, and the mPFS was 6.
9 months
.

Comments: Adagrasib's PDUFA date is December 14, 2022, and the listing is gradually approaching
.
However, the efficacy advantage of Adagrasib over AMG510 is not obvious, but the toxicity is significantly increased, and the phase II KRYSTAL-1 study showed that G3 TRAE reached 43%.

The combination with cetuximab in the treatment of colorectal cancer has excellent efficacy, and we look forward to the data of subsequent registration clinical trials
.

(3) JAB-21822 is a potent and irreversible KRAS G12C allosteric inhibitor independently developed by Jacobio, JAB-21822 locks KRAS G12C in an inactive state by covalently binding to the 12-position mutated cysteine residue of KRAS G12C, thereby blocking KRAS-dependent signal transduction, inhibiting the proliferation of tumor cells, and inducing apoptosis
.

At ASCO 2022, Jacobio disclosed a phase I/II trial of JAB-21822 in KRAS G12C-mutated non-small cell lung cancer, with an ORR of 56.
3% and a DCR of 90.
6%
in 32 patients with KRAS G12C-mutated non-small cell lung cancer.
In the QD dose group of 400 mg/d and 800 mg/d, the ORR was 66.
7% and the DCR was 100%.

(4) IBI351 is a highly effective oral new molecular entity compound under Innovent Biologics/GenFleet, which effectively inhibits the protein-mediated GTP/GDP exchange and lowers the activation level
of KRAS protein by covalently irreversible modification of the cysteine residue of the KRAS G12C protein mutant.
At ASCO 2022, Innovent Biologics disclosed a Phase I dose-escalation study
of IBI351 monotherapy in patients with advanced solid tumors.
A total of 31 participants with advanced malignancies who had failed or tolerated standard treatment in the study were enrolled, among which 12 patients with non-small cell lung cancer received IBI351 at a dose of 700mg QD and above, with an ORR of 50% and a DCR of 83.
3%.
Five colorectal cancer patients were treated with IBI351 with an ORR of 40% and a DCR of 60%.

In terms of safety, 12.
9% of participants developed grade 3 TRAEs, no grade 4 and 5 TRAEs, and TRAEs leading to treatment discontinuation
.

(5) D-1553 is a small molecule KRAS G12C
under Ifang.
At the 2022 WCLC, Yifang Biotech disclosed the phase I clinical data of D-1553, and 79 patients with KRAS G12C mutation who had previously received ≥ 2-line systemic therapy had an ORR of 37.
8%, a DCR of 91.
9%, and an mPFS of 7.
6m
.
In terms of safety, no dose-limiting toxicities were observed, and no treatment-related fatal adverse events
occurred.

SUMMARY SUMMARY

The research and development of KRAS G12C inhibitors has gradually entered the deep water area, from monotherapy to combination therapy, the efficacy has gradually improved, which is expected to provide new treatment methods
for patients with NSCLC and CRC with KRAS G12C mutations.
At present, only sotorasib has been approved for marketing in the world, and Adagrasib's PDUFA date is December 14, 2022, and it is expected to be listed
by the end of the year.
Focusing on China, dozens of companies are deeply engaged in KRAS G12C inhibitors, among which Jacobio, Innovent Biologics, Yifang Biologics and other clinical progress are in the forefront, and their drugs have shown potential good clinical efficacy
.
Looking forward to the subsequent single-agent and combination data of KRAS G12C inhibitors, including the OS advantages
that everyone is particularly concerned about.