KRAS G12C mutant NSCLC finally has a targeted drug: sotorasib approved

KRAS mutation is one of the most common oncogenic driver genes.
KRASG12C mutation can occur in about 13% of patients with lung adenocarcinoma.

In the past few decades, a number of drug researches aimed at the development of KRAS mutant genes have come to an end, and KRAS mutations have also become a "non-drugable" target.

In 2019, sotorasib turned out to break this dilemma with amazing data.

Sorasasib (AMG510) is a reversible and highly selective first small molecule inhibitor targeting KRAS p.
G12C.

On May 28, local time, the U.
S.
Food and Drug Administration (FDA) announced the accelerated approval of sotorasib for locally advanced or metastatic non-small cell lung cancer (NSCLC) patients with KRAS G12C mutation who had received at least one systemic treatment in the past.

The approval is mainly based on the Phase I/II CodeBreaK100 clinical trial (NCT03600883).

Research data shows that among 124 patients with locally advanced or metastatic NSCLC who have undergone disease progression after receiving immune checkpoint inhibitors and/or platinum-based chemotherapy, sotorasib has an objective response rate (ORR) of 36% and a disease control rate (DCR) It was 81%, the median duration of response was 10 months, and 58% of patients had a duration of response (DOR) ≥ 6 months.

At the upcoming 2021 ASCO annual meeting, the CodeBreaK100 study will be announced to expand the efficacy data of the patient subgroup with key baseline characteristics and biomarkers2.

The enrolled patients took orally sotorasib 960mg once a day.

The researchers used tissue samples to analyze KRAS p.
G12 C mutation allele frequency (MAF) and tumor mutation burden (TMB) through next-generation sequencing (NGS).Use tissue and/or plasma samples to determine the mutation status of individual genes through NGS.

The correlation between remission and KRAS p.
G12 C MAF, TMB, or co-mutation was analyzed in a subgroup of patients with corresponding results.

Logistic regression was used to obtain OR (odds ratio, 95% CI) to report the correlation between MAF and response.
The dependent variables were the respondent's log odds ratio and the independent variable of MAF, and the unit was 10%.

The primary study endpoint is ORR, and secondary endpoints include progression-free survival (PFS), overall survival (OS), and safety.

The ORR of each subgroup is shown in the figure below: for NSCLC patients who have not received immunotherapy, the use of KRAS inhibitors benefits better, with an ORR of 45.
5%; for NSCLC patients with co-mutation of KRAS and TP53, the ORR is 39.
3%; For NSCLC patients with co-mutation of KRAS and STK11, the ORR was 40%; for NSCLC patients with co-mutation of KRAS and KEAP1, the ORR was 20%.

Sorasasib is the first approved and currently the only targeted drug for locally advanced or metastatic NSCLC patients with KRAS G12C mutations, which is a milestone.

Other KRASG12C inhibitors including MRTX849, GDC6036, LY349944 and JNJ-74699157 are under study.

References: 1.
FDA approves first targeted therapy for lung cancer mutation previously considered resistant to drug therapy.
News release.
May 28, 2021.
Accessed May 28, 2021.
https://bit.
ly/3c172Ah2.
Overall survival and exploratory subgroup analyses from the phase 2.
CodeBreaK 100 trial evaluating sotorasib in pretreated KRAS p.
G12C mutated non-small cell lung cancer.
2021 ASCO.
Abstract #:9003