Sotorasib: A new triumph of drug discovery in cancer!

KRAS is among the genes most often affected by mutation and is one of the oncogenes (cancer genes) in human cancers. Until recently, it was considered undruggable. However, early results with the experimental KRAS inhibitor sotorasib, a new drug candidate in an early clinical trial, have offered hope for cancers carrying a common KRAS mutation, particularly non-small cell lung cancers (NSCLC).

Presented at the ESMO Virtual Congress 2020 and simultaneously published in NEJM, the phase 1 CodeBreaK 100 clinical trial found that sotorasib, developed for the KRAS p.G12C mutation, showed encouraging activity against advanced, heavily pretreated NSCLC and other solid/organ tumors.

The most striking result of the study was as follows: sotorasib monotherapy produced a confirmed objective response in 19 of 59 patients with NSCLC (32.2%) and disease control in 52 (88.1%).

It was also found that, in addition to the absence of dose-limiting side effects and drug-related deaths, fewer than 20% of patients experienced more serious (grade 3 or higher) side effects. These are very favorable safety data for a cancer drug.

The fewer-than-expected side effects were attributed to sotorasib's highly specific binding to KRAS G12C and the presence of KRAS G12C only in the tumor.

An important milestone

KRAS had been known for 30 years to play a critical role in cancer development. However, because of the unique biology of KRAS mutations, it had not been possible to target and silence it with an anticancer agent.

The discovery of agents that effectively target the KRAS G12C mutation is only a beginning. It offers hope that the ability to target not only other KRAS mutations but also other mutations previously considered unsuccessful targets may be achievable.

Although KRAS p.G12C mutations are reported most frequently in non-small cell lung cancers (NSCLC), they are also found in other solid tumors, particularly colorectal cancers. Their prevalence is 13% in NSCLC and 1-7% in colorectal cancers.

What makes KRAS difficult to target with a drug is its strong binding to guanosine triphosphate (GTP), a basic building block of RNA synthesis.

Study details

CodeBreaK 100 researchers enrolled patients whose tumors all carried the KRAS p.G12C mutation and represented 13 different locally advanced or metastatic solid/organ tumor types.

The trial started at 180 mg and gradually increased to 960 mg.

The study's lead author, Dr. David S. Hong, and colleagues reported results for a total of 129 patients: 59 had NSCLC, 42 colorectal cancer, and 28 other tumor types, although the main focus was on patients with NSCLC.

After a mean follow-up of 11.7 months, 14 of the 59 patients with NSCLC were still receiving treatment as of June 2020, while 45 had stopped because of disease progression (35 patients), death (5), patient request (4), or side effects (1).

As noted, no dose-limiting side effects or treatment-related deaths were reported.

Serious (grade 3 or 4) treatment-related side effects were reported in 18.6% of patients. The only grade 4 treatment-related event was elevated alanine aminotransferase (ALT) in one patient. Grade 3 events included elevated liver enzymes in 9 patients, increased alkaline phosphatase in 2 patients, anemia in 1 patient, and increased gamma-glutamyl transferase, decreased lymphocyte count, hepatitis, and hyponatremia (low sodium), each in one patient.

Responses at all dose levels

Confirmed partial response rates were reported for patients with NSCLC treated at all dose levels. The objective response rate was 32.2% in patients receiving 180 mg and 35.3% in those receiving 960 mg.

Median progression-free survival was 6.3 months.

Presenting the study, Dr. Hong reported on a patient previously treated with immunotherapy among 5 lines of treatment. This 59-year-old man had also received radiotherapy for brain metastasis. Sotorasib produced a complete response in target lesions and significant shrinkage of the brain metastasis. After responding to treatment for 1.5 years, the patient experienced cancer progression with other metastases.

The median response duration was 10.9 months for patients with partial responses and 4 months for those with stable disease.

Other tumors and possible combinations

Of 42 patients with colorectal cancer carrying the KRAS p.G12C mutation, 3 (7.1%) had a partial response. Partial responses were also seen in one patient each with melanoma and tumors of the appendix, endometrium (uterus), and pancreas.

However, some tumors are resistant to KRAS inhibition, and while scientists develop KRAS-inhibiting drugs, they are also identifying mechanisms of drug resistance.

Another recent study showed that colorectal cancer cells with KRAS G12C mutations had higher baseline epidermal growth factor receptor (EGFR) activity than NSCLC cells, leading to a rapid rebound in mitogen-activated protein (MAP) kinase signaling and resistance to KRAS G12C inhibition. This observation explains sotorasib's lower observed clinical activity in patients with colorectal cancer, a problem that appears potentially solvable by combining sotorasib with an EGFR inhibitor (such as cetuximab).