First KRAS targeted drug to control advanced lung cancer reaches 80%

First KRAS targeted drug to control advanced lung cancer reaches 80%

First KRAS targeted drug to control advanced lung cancer reaches 80%.   

Good Phase 1 Results

In September last year, the results of a Phase 1 clinical trial published in the New England Journal of Medicine (NEJM) aroused the enthusiastic attention of people in the industry. The reason is that this study is aimed at a target that was previously considered unavailable as a drug— -KRAS.

As we all know, the development of targeted cancer therapy in recent years has been changing rapidly, and new targets have been discovered constantly, and new targets mean the possibility of new drugs. The difference of KRAS is that it is not a new target, but a very old target, so old that it appears in most medical textbooks and becomes an exam question for medical students.

Like many oncogenes, mutations in KRAS can cause cells to become cancerous and continue to proliferate. KRAS mutations are the most common cancer driver genes and are related to many common cancers including lung cancer, colorectal cancer, pancreatic cancer, and leukemia. Among them, one-quarter of lung cancer patients and one-third to half of colorectal cancer patients carry KRAS. mutation.

The influence of wild-type KRAS and mutant KRAS on cell proliferation and differentiation (picture from the Internet)

Such “old” and common targets have not been targeted drugs for nearly 40 years. Although there are no targeted drugs, the FDA approved several KRAS mutation tests for colorectal cancer patients in 2012. Why do you want to test if there is no medicine? This is because, unlike other oncogene testing purposes, testing for KRAS mutations is not to predict who will get better results, but to predict who will have worse therapeutic effects.

Patients with KRAS mutations have no effect or poor effect on many targeted therapies, such as targeted therapy for epidermal growth factor receptor (EGFR). Generally speaking, the EGFR targeted therapy drug erlotinib can achieve a 60% response rate in EGFR mutation-positive lung cancer, but if it also carries the KRAS mutation, the response rate drops to less than 5%.

Why KRAS can only act as a “bad guy checker”, but there has been no suitable targeted therapy? According to the corresponding author of the NEJM paper, Dr. Bob Li (Li Tingkan), an expert on thoracic tumors and new drug development at the Memorial Sloan Kettering Cancer Center (MSK Sloan) in the United States, this is related to the structure of the KRAS protein, a KRAS gene product: “Most proteins It has a blocky, irregular shape with many cracks and pockets into which drugs can be wedged. When this happens, the drug can act as a key to lock the protein and shut down its activity. In contrast, the KRAS protein It’s very smooth, no cracks and pockets are found. Therefore, if you can’t find a keyhole, you can’t make a key.” So KRAS was once considered incompatible.

Overview of Phase 2 Clinical Trials

Following the gratifying results of the Phase 1 clinical trial, Bob Li announced the results of the successfully completed Phase 2 clinical trial at the just-held World Lung Cancer Conference. This study is called “CodeBreak 100” for short. According to the results of clinical trials, sotorasib, the first KRAS G12C inhibitor of its kind, showed an early, deep and long-lasting response in the treatment of advanced non-small cell lung cancer (NSCLC) with KRAS G12C mutations.

Screenshot of the World Lung Cancer Conference report (picture from the official website of the World Lung Cancer Conference)

Bob Li’s report was published in the chairman’s seminar of the World Lung Cancer Conference. At the meeting, he was pleased to announce that the drug had obtained the Breakthrough Therapy Mark from the U.S. Food and Drug Administration (FDA). The bureau submitted regulatory documents, and the Phase 3 clinical trial “CodeBreak 200” has also begun to recruit patients.

According to the results of the registered Phase II CodeBreaK 100 trial, sotorasib, the first of its kind KRAS G12C inhibitor, showed an early, deep and long-lasting response in the treatment of advanced NSCLC with KRAS G12C mutations.

In the Phase I CodeBreaK 100 trial, Sotoracide showed durable clinical benefits in a cohort of 59 NSCLC patients who had received multiple treatments. The objective response was 32.2%, and the median response time was 10.9 months. The median progression-free survival was 6.3 months.

The phase II trial included 126 patients with locally advanced or metastatic NSCLC with KRAS G12C mutations. These patients continued to progress after using 3 standard therapies; 81% of the included patients had previously used platinum-based chemotherapy and PD-L1 inhibitors. The primary endpoint is the overall response rate assessed by an independent central review.

The dose of sotoracide is 960 mg once a day until the disease progresses.

Bob Li said that of the 126 patients included, two patients had no measurable lesions at the time of enrollment and were excluded from the response assessment according to the central radiological review. Among the remaining 124 patients, the overall response rate (ORR) was 37.1%, including 3 patients with complete responses and 43 patients with partial responses. The disease control rate was 80.6%.

81% of patients observed varying degrees of tumor shrinkage. Among all responders, the median percentage of optimal tumor shrinkage was 60%.

72% of patients had an early and rapid response at the first CT scan at 6 weeks.

The median time of objective response was 1.4 months, and the median time of response was 10 months. As of the data cutoff, 43% of the responders were still receiving treatment without progress.

The median progression-free survival was 6.8 months, which was consistent with the previous phase I results.

According to Bob Li, sotoracib is well tolerated, there is no death due to treatment, and the incidence of treatment-related grade 3 or 4 adverse events, treatment discontinuation and dose adjustment is very low.

Treatment-related adverse events are generally mild and can be controlled; most of them are grade 1 or 2. There was a grade 4 toxicity event, and the patient reported dyspnea and pneumonia.

Treatment-related adverse events caused about one-fifth (22.2%) of patients to adjust the dose, and 7.1% of patients stopped treatment.

The researchers also performed exploratory biomarker analysis using tumor biopsies before treatment. Sotorasi’s response can be seen in each subgroup. PD-L1 TPS is less than 1%, and the overall response rate is 48%; PD-L1 TPS is 1% to 49%, and the overall response rate is 39%; TPS is greater than 50%, and the overall response rate is 22%.

Bright future

The results of CodeBreak 100 aroused an enthusiastic response from the participants. Dr. Pasi A. Jänne of the Dana Farber Cancer Institute congratulated the researchers when commenting on this study and announced that the KRAS G12C inhibitor has finally appeared.

To illustrate the importance of these findings, Dr. Jänne pointed out that half of the patients with KRAS mutations have KRAS G12C mutations, and the number of patients in this subset is more than the sum of ALK, ROS1, RET, and TRK 1/2/3 mutations. .

(source:internet, reference only)

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